Volume 7, Issue 1 (3-2019)                   J Surg Trauma 2019, 7(1): 3-14 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Amouzeshi A, Pourbagher-Shahri A M. Effects of endocannabinoid system, synthetic and nonsynthetic cannabinoid drugs on traumatic brain injury outcome: a narrative review. J Surg Trauma 2019; 7 (1) :3-14
URL: http://jsurgery.bums.ac.ir/article-1-165-en.html
MD, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
Full-Text [PDF 1005 kb]   (921 Downloads)     |   Abstract (HTML)  (4208 Views)
Full-Text:   (1864 Views)

 

Effects of endocannabinoid system, synthetic and nonsynthetic cannabinoid drugs on traumatic brain injury outcome: a narrative review

Ahmad Amouzeshi1, Ali Mohammad Pourbagher-Shahri2*

1Associate Professor, Department of Cardiac Surgery, Birjand University of Medical Sciences, Birjand, Iran

2MD, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran

Received: August 29, 2018             Revised: December 09, 2018         Accepted: February 19, 2019

Abstract

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. The initial injury is followed by a series of secondary processes that can further harm the injured brain and worsen the outcome. The endocannabinoid system (ECS) consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g., Cannabinoid receptor type 1 and Cannabinoid receptor type 2), as well as transporters, and enzymes. Dexanabinol (HU-211) is a synthetic cannabinoid with cerebroprotective effects devoid of cannabimimetic effects, which exhibits the pharmacological properties of N-Methyl-D-aspartate receptor antagonist. The increase in the brain levels of endocannabinoids in the pathogenic events of brain injury suggests that this system plays a role in compensatory repair mechanisms. In recent year, the therapeutic effects of cannabinoid manipulative drugs have been numerously studied through the manipulation of the ECS in TBI. Therefore, the literature review was performed to assess the therapeutic effects of ECS manipulation, cannabinoid-derived drugs, and HU-211 in traumatic brain injury pathology. The ECS possesses promising effects in the treatment of diverse TBI pathologies through releasing endogenous ligands and changes in cannabinoid receptors activity or both. Preclinical studies suggest that the ECS has many targets for therapeutic agents that might help decrease TBI pathologic effects and should be considered for developing novel drugs. Furthermore, more clinical trials with larger populations and more extended follow-up periods should be performed for a better understanding of the effects of ECS manipulative drugs.

Key words: Brain injuries, Cannabinoids, Cannabinoid receptors, Endocannabinoids, HU 211, Traumatic


Introduction

Traumatic brain injury (TBI) is defined as “an alteration in brain function or other evidence of brain pathology caused by an external force” (1). The diagnosis in most cases is obtained through the evaluation of clinical symptoms, neurological signs, as well as neuroimaging findings (2). The TBI is categorized as mild, moderate, or severe based on 1) the initial Glasgow Coma Scale (GCS) score (A GCS score of 13-15 denoting a mild TBI, GCS score of 9–12 showing a moderate TBI, and GCS score of 3–8 demonstrating a severe TBI) and 2) the duration of loss of consciousness (LOC) or coma, as well as the duration of posttraumatic amnesia (PTA). In moderate to severe TBI, the patients tend to have a more prolonged LOC or coma and sustain PTA symptoms for a longer period (2).

The TBI-induced alterations in brain functions can lead to many symptoms, including the loss or decline of consciousness, amnesia for events immediately after the injury or before it (retrograde), neurological deficits, such as paralysis or weakness, spasticity, poor balance, visual changes, dyspraxia, paresis/plegia, sensory impairment, aphasia, and mental status changes at the time of the injury (e.g., confusion, disorientation to time and location, and slow thinking,) (3).

The TBI is a significant cause of morbidity and mortality worldwide. The overall worldwide incidences of TBI are 80% (mild), 10% (moderate), and 10% (severe). Only in the United States, over 1.7 million people suffer from TBI every year with over 50,000 deaths and at least one-third of survivors facing long-term disabilities (4-6). In 2012 In Europe, TBI was responsible for over 37% of all deaths related to injury (7). The highest rate of mortality due to brain injury occurs in the population older than 65 years of age. The overall rate of TBI in men is 29% higher than that in women (8). In cases of severe head injury, brain damage sometimes is immediate and irreversible.

The TBI is associated with complex pathophysiologic processes demonstrated as two types, including primary and secondary injury. Mechanical forces that physically disrupt the brain tissue itself are called primary injuries. Secondary injuries occur hours and days after
the primary injuries and consist of diverse pathophysiologic processes and phenomena, such as hypoperfusion, cellular dysfunction, oxidative injuries, and disruption of blood-brain barrier (BBB)
(9).

One of the central elements in the pathogenesis of secondary injury is brain edema. Elevated intracranial pressure (ICP) and decreased cerebral perfusion pressure are mainly due to brain edema (10). There are other processes that cause further damage in TBI. One of these processes is a phenomenon known as excitotoxic injury, which is the overload of excitatory amino acids, such as glutamate and aspartate in the extracellular fluid and cerebrospinal fluid leading to acute neuronal and astrocytic swelling, as well as delayed cellular damage, or cell death via cellular necrosis and apoptosis (11).

An increase in the severity of TBI is often associated with several other injuries. These joint injuries can directly affect secondary injury and the associated pathology. The results of some studies showed that the combination of TBI and hemorrhagic shock could cause more hippocampal damage, compared to just TBI, a condition which is associated with increased secondary ischemia (12-15). In the chronic period after TBI, there are multiple neurotransmitter deficits and cellular dysfunction. Brain in the chronic period after TBI is responsive to neuroplasticity, repair, and recovery.

The resolution of cerebral edema and regulation of blood flow take place in the early phases of TBI recovery. Synaptic plasticity, axonal sprouting, and cortical reorganization occur in the reversal process of diaschisis, which takes place after the early phases of TBI recovery (2). Proper rehabilitation strategies and pharmacologic interventions can manipulate late recovery (2, 16-18). The TBI is associated with direct and indirect costs. Direct costs involve the financial requirements for medical care, whereas indirect costs refer to those associated with the loss of productivity in individuals suffered from TBI, the family members that take care of them, and the costs of reduced participation in complex leisure or recreational activities (16, 19).

It has been reported that TBI patients suffer from at least one issue in the next year after their hospitalization (20). Over the past few decades, a better understanding of the TBI pathophysiology has helped develop new management guidelines and treatment paradigms that result in better clinical outcomes. However, nowadays, the treatments aim at limiting the neurochemical cascade associated with secondary brain injury. However, in the developed countries, a significant drop from 50% to 20-30% in mortality rate following severe TBI has been achieved through all efforts over the past three decades (21).

Therapeutic protocols in this regard are mainly physiological monitoring and support, performing surgical intervention when needed, as well as medications, such as mannitol, hypertonic saline, sedatives, and anticonvulsants (22). Decompressive craniotomies also have recently improved survival rate; however, the ongoing rage debate in applying this procedure is which patients are candidates for this procedure and what is the appropriate timing (23, 24).

“Cannabinoid” refers to a set of naturally occurring aromatic hydrocarbon compounds in Cannabis sativa (25). Nonetheless, today, it refers to a broad set of chemicals that their pharmacological actions or structures closely mimic those of
plant-derived cannabinoids
(26). Two types of cannabinoid receptors have been identified so far, including cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2).

The endocannabinoid (ECS) system consists of the ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g., CB1, CB2, possibly the transient receptor potential cation channel subfamily V member 1, and
G protein-coupled receptor 55), transporters
and enzymes, which are responsible for the
synthesis (e.g., N-acyl-phosphatidylethanolamine phospholipase D, diacylglycerol lipase) and degradation of these lipid mediators (i.e., fatty acid amide hydrolase and monoacylglycerol lipase]
(27, 28).

There are three predominant categories of cannabinoids that are currently in use, including
A) plant-derived phytocannabinoids
(29), B) synthetically-produced cannabinoids (30) or recreational drugs (31), and C) endogenous cannabinoids (Anandamide) (32) and 2-AG (33)). The ECS has several functions in the brain under both physiological and pathological conditions. Anandamide (32) and 2-AG (33), which are produced in the brain as primary ligands, activate both CB1 and CB2. The 2-AG acts as a high efficacy agonist at CB1 and CB2 , while anandamide behaves as a partial agonist (34).

Endogenous ligands are responsible for the functional selectivity of the ECS. Neurotransmitter systems in the body traditionally generate the differential activation of signaling pathways via the activation of receptor subtypes using one neurotransmitter (35). However, in the ECS, the endogenous ligands of ECS receptors are responsible for such signaling specificity. Most of the psychomimetic effects of cannabis are mediated via a CB1 and its main psychoactive constituent, tetrahydrocannabinol (THC), as well as many other central nervous system (CNS) active cannabinoids. The types and location of targeted cells determine the outcome of cannabinoid receptor signaling (26).

The neurons in CNS areas, such as the cerebral cortex, hippocampus, and caudate putamen, are where CB1 are predominantly expressed (26, 36). On the other hand, CB2 are mainly expressed in nonneuronal cells, such as immune cells, microglia in the CNS, macrophages, monocytes, CD4C and CD8C T cells, as well as B cells in the periphery (37). Although these receptors produce no psychoactivity, they are expressed on neurons but to a much less extent than CB1 (38). The activation of CB1 and CB2 attenuates the inflammatory response by inhibiting the release of pro-inflammatory mediators, decreasing leukocyte chemotaxis, and extravasation into the brain parenchyma (39).

The CB2 receptor agonists also decrease cytochrome-C release, inhibit apoptosis, and exert anti-inflammatory effects in a broad range of animal models (40, 41). The heterogeneous distribution of CB1 and CB2 throughout the brain and periphery probably is the reason that they impact a wide variety of physiological and psychological processes, such as memory, anxiety, and pain perception (42), many of which are influenced by TBI. It has been well-documented that pathogenic events, such as epileptiform seizures and neuronal excitability, due to the events, including trauma, significantly activate the ECS (43). Because the ECS is activated in response to such events, it can be suggested that it is part of the brain’s compensatory repair mechanism mediated via CB receptor signaling (44).

 The main strategy for investigating the potential neuroprotective effects of ECS in TBI animal models is via enhancing ECS signaling with selective amplification of anandamide and 2-AG levels by pharmacological inhibitors for ECS catabolic enzymes (26). Dexanabinol (HU-211) is a synthetic nonpsychotropic cannabinoid (45) that act as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (46). Moreover, it has antioxidant (47) and anti-inflammatory properties (i.e., TNF-α blocking) (48). It has been shown that HU-211 is effective in some animal models of traumatic and ischemic brain injury without any signs of overt toxicity at pharmacologically relevant doses (49, 50).

Drug therapies for TBI are yet to be proven and once reaching the clinical trials, there are many transitional problems (51-53). The therapeutic strategy of few drugs used in TBI is towards the manipulation of endogenous systems that are present and active from the beginning of the injury process. The ECS has a vast and diffuse area for effectiveness, and these features give the ECS a significant power to protect the CNS against pathologic processes.

The complicated pathology of TBI and the existence of any drugs for its definite cure have emerged numerous studies to examine new therapeutic strategies based on the manipulation of the ECS. Considering these, it was decided to review these scientific pieces of literature to answer some questions, such as A) To what changes do the modifications in a specific part of the ECS system relate in TBI pathologies?, B) Whether the observed effects in preclinical studies are present in the clinical studies?, C) What complications are associated with the drugs that modify the ECS system and whether they are safe for the human use?, and D) What do these performed studies lack and what has to be considered in future studies to obtain more strong evidence for determining new therapeutic strategies for TBI considering the ECS modification?

Methods

The authors of this study tried to become close to the steps of a systematic review; however, they do not claim for performing a systematic review. The literature search was carried out using databases and search engines listed as PubMed, Scopus, Google Scholar, ScienceDirect, and Cochrane Library between 1990 and 2018. The literature search was performed using the keyword ‘traumatic brain injury’ in conjunction with each of the following keywords, including ‘endocannabinoid system,’ ‘cannabinoid,’ ‘dexanabinol,’ and ‘cannabinoid-derived drug.’ Original research articles and review articles in the English language were included.

Moreover, the articles in other languages with English abstract were included if needed. Other types of articles were excluded, such as the letters to editor, commentary, book review. Furthermore, the articles that were not published yet were excluded. A manual search in the reference sections of relevant review articles was also performed to identify additional studies. Most of the articles were included for final consideration. Records were firstly refined based on title and abstract. Then the remained articles were assessed based on the full texts. Finally, based on the quality appraisal of remained articles using Critical Appraisal Skills Program checklists, rigorous articles were chosen for final analysis.

 

Endocannabinoid system

Preclinical Studies

The CB2 has shown a significant and endogenous role in regulating inflammation. Initial traumatic insult induces an inflammatory response that leads to neuronal damage. In a study carried out by Amenta et al. (54), synthetic selective CB2 receptor agonists (i.e., 0-1966 and JWH-133) and a selective CB2 receptor antagonist or a vehicle solution were used in an experimental model of TBI in rats to investigate the effects of CB2 stimulation, blockade, and deletion on the neurovascular inflammatory responses to TBI.

Treatment with CB2 receptor agonist attenuated tumor necrosis factor-alpha (TNF-α) protein levels and increased inducible nitric oxide synthase (iNOS) mRNA expression, while the genetic deletion of CB2 resulted in substantial increases in iNOS expression. The CB2 stimulation ameliorated posttraumatic inflammation and protected the neurons, while the blockade or deletion of the CB2 increased the inflammation. The 2-AG is an endocannabinoid and an endogenous receptor agonist of CB₁ identified both in the periphery and brain.

Reactive oxygen species (ROS) and TNF-α are major contributors to the pathophysiology of brain injury. Brain edema leads to an elevation in intracranial pressure; therefore, measuring intracranial pressure and water content can be applied to determine the severity of brain edema. A study reported that 2-AG suppressed the formation of ROS and TNF-α by murine macrophages in vitro after stimulation with lipopolysaccharide (55).
In another study
(56), synthetic 2-AG was administrated 15 min after the experimental TBI in mice. The results showed that the levels of endogenous 2-AG were significantly increased, and the treatment with 2-AG reduced brain edema by 50%.

The clinical status of the animals was evaluated by testing motor and behavioral functions 1 and 24 h after the injury. The 2-AG treatment resulted in a good and fast recovery within 24 h after the injury, although the evaluations on the following days showed no significant improvement. Neuronal cell death was evidenced by the infarct volume around the site of injury, which was reduced by 2-AG treatment. Moreover, 2-AG treated animals showed a lower loss of neurons, compared to vehicle-treated animals.

Finally, to confirm that 2-AG effects were mediated via a CB1, the administration of a CB1 receptor antagonist demonstrated a dose-dependently attenuation of 2-AG beneficial effects. The results of the aforementioned study showed that 2-AG administration in TBI mice model generated cerebral protection via decreasing neuronal excitotoxicity, inhibiting the production of TNF-α and ROS, and lowering cerebral vasoconstriction (56).

In another study, repeated treatments with a CB2 receptor agonist on BBB integrity, neuronal degeneration, and the behavioral outcome were performed on a murine model of TBI (57). Cannabinoid agonist significantly decreased BBB permeability (indicated by a reduction in sodium fluorescein uptake) and reduced the number of degenerating neurons, compared to the vehicle-treated group. In addition, the improvement was observed in animals treated with cannabinoid agonist on Rota-rod and open field test, which was associated with a prolonged reduction in macrophage/microglia cell counts.

Taken together, cannabinoid agonist treatment after the brain injury attenuated BBB disruption and neuronal degeneration and induced prolonged protective effects on behavior and macrophage/ microglia cell response. Another study examined the acute effects of CB2 modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI (58). After using cortical contusion injury (CCI) surgery to induce TBI or sham surgery, animals received vehicle or 0-1966 as a CB2 receptor agonist at 1 and 24h after the injury.

Rota-rod, forelimb cylinder, and open field tests were performed before and 48 h after sham or CCI surgery. The mice who received 0-1966 showed significantly improved locomotor performance and exploratory behavior, compared to vehicle-treated mice. Furthermore, the mice treated with CB2 receptor antagonist demonstrated a significant decrease in the cerebral edema, number of perivascular areas of substance-P immune-reactivity, and number of activated macrophages/microglial cells in the brains, compared to vehicle-treated mice.

Altogether, selective CB2 activation showed neuroprotective effects on brain injury. The TBI patients often suffer from cognitive deficits after the incident, and currently, no effective and definite treatment is available. Some of the pathophysiological mechanisms linked to post-TBI cognitive deficits are excitotoxicity, neuroin-flammation, and neuro-metabolic dysfunctions with an associated increase in ROS (59).

In one experiment, the effects of CB1 receptor agonist was investigated on learning and memory-dependent behaviors after an experimental TBI in rats (60). The treatment with CB1 receptor agonist and arachidonyl-2′-chloroethylamide (1 mg/kg, daily, intraperitoneal) showed to protect and rescue deficits in learning and memory abilities. The CB2 are expressed at low levels in the brain and have higher concentrations in microglia than neurons; therefore, they are nonpsychotropic in contrast to CB1 (52-54).

The increased expression of CB2 are observed in activated microglia (41, 61-65), and therefore, the drugs that act on CB2 can be selectively used to target microglia for therapeutic purposes. The CB2 receptor inverse agonists stabilize CB2 in an inactive state that ultimately activates microglia from M1 state to M2 state. Microglia activation exists in two stages, including 1) M1 state associated with the production of ROS and pro-inflammatory cytokines, as well as 2) M2 state anti-inflammatory and associated with wound healing and debris clearance (66).

In the setting of TBI, activation of CB2 leads to M1 microglial activation that can be harmful to the recovery process and increases the secondary damage. Braun et al. (67) used a selective CB2 receptor agonist (i.e., GP1a) and CB2 receptor antagonist (i.e., AM630) in a murine model of TBI to study the effects of activation of CB2 in neuroinflammation and neurovascular injury. The GP1a administration (1–5 mg/kg) attenuated
pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes.

On the other hand, CB2 receptor antagonist worsened the outcomes after TBI. The results showed that CB2 modulation had a critical role in peripheral immune cells in recovery from TBI, improved motor functions and neurological outcomes, and reduced anxiety after experimental TBI. In another study performed by Anton Reiner et al. (68), daily treatment with a CB2 receptor inverse agonist (i.e., SMM-189), which started two weeks after establishing an animal model of TBI, attenuated the motor, visual, and emotional deficits.

In another experiment, focal blast model was used to create mild TBI in mice. The goal of the aforementioned study was to find whether TBI-induced loss of neurons in brain regions is linked to motor functions and fear control, as well as the administration of SMM-189 can be effective in rescuing neurons and protecting against functional deficits (69). The obtained results of the study showed that fearfulness after mild TBI might result from the loss of fear-suppressing neuron types in the basolateral amygdala (BLA), and SMM-189 yielded 50-60% rescue of Thy1+ and PARV neuron loss in the BLA. Therefore, SMM-189 may reduce fearfulness after mild TBI.

Overall, SMM-189 rescued damaged neurons and alleviated functional deficits that resulted from TBI, and these actions were induced by selectively modulating microglia to the beneficial M2 state. Cognitive and emotional deficits associated with mild TBI underline the involvement of medial prefrontal cortex (mPFC) and the hippocampus. It should be noted that these two structures are of central importance for cognitive and emotional functions (70-72). Oscillatory neurons activity in specific frequencies synchronize the activity of neurons within and between the structures of mPFC, as well as hippocampus, and this transient synchronization plays a role in cognitive and emotional processes (73-81).

In a study carried out by Yu Liu et al.
(82), multi-site multi-electrode detectors were connected to awake and head-fixed mice to record oscillatory neuronal activity in local field potentials to determine if the functioning of these regions was abnormal after mild TBI in an experimental model and administration of a CB2 receptor inverse agonist (i.e., SMM-189). Significant abnormalities in oscillatory neuronal activity patterns in the CA1 of hippocampus and mPFC were observed after mild TBI.

The SMM-189 mitigated functional deficits and neuronal injury and reversed most of the observed neurophysiological abnormalities. These changes by SMM-189 are thought to be a result of biasing microglia from the pro-inflammatory M1 state to the prohealing M2 state. Mild and severe TBI can result in two and seven times higher relative risk of developing posttraumatic epilepsy (PTE)
in suffering individuals than their healthy counterparts, respectively
(83).

Endocannabinoids have been studied for their anticonvulsant properties (84). In a study conducted by Xiu Wang et al. (85), after establishing the TBI model in rats, they were monitored for 12 months for the development of PTE. After behavioral monitoring of PTE and nonPTE rats and comparing the changes between two groups, it was observed that the expression of CB1 and its ligand synthetase (i.e., 2-AG) in the PTE group were significantly higher than those in the nonPTE group 12 month after TBI. These findings suggest that the ECS may have a vital role in the development of PTE after TBI, and the modulation of this system can be a therapeutic option.

Another study has investigated the effects of CB2 in the actions of Leptin. Mice received an antagonist of CB2 (i.e., AM630) or the vehicle, then the weight-drop model was used to induce TBI, and after that they received Leptin or vehicle treatment. Leptin alleviated TBI-induced neurological deficits and recovered the expression of cannabinoid receptors, axonal injury markers, and neuroinflammatory components. All these effects generated by Leptin were prevented or decreased when it was administrated in combination with AM630. These results suggested that CB2 activity has an important role in TBI pathophysiology and recovery (86).

Minocycline, as a highly lipophilic derivative of the antibiotic tetracycline, can suppress microglial activation, reduce cerebral edema, as well as lesion volume, and induce persistent neuroprotection in experimental TBI models (87-91). Minocycline-mediated neuroprotection mechanism has been proposed to be related to the inhibition of microglial activation (92), reduction of activation of the p38 mitogen-activated protein kinase (93), or the attenuation of pro-inflammatory cytokines (94).

To investigate the ECS relation with neuroprotection effects of minocycline, Lopez-Rodriguez et al. (95) studied the involvement of CB1 and CB2 in the effects of minocycline on edema and neurological impairment in a mouse-TBI model. Selective CB1 and CB2 receptor antagonists (i.e., AM251 and AM630, respectively) were administrated to the animals who received minocycline. The results showed that the protective actions of minocycline were all prevented by both CB1 and CB2 receptor antagonists suggesting that the activation of cannabinoid receptors are required for the neuroprotective effects of minocycline. Moreover, the activation of these receptors can induce protective effects on the nervous system after injury.

 

Clinical Studies

In a clinical trial, patients with severe TBI were treated with a dual CB1/CB2 receptor agonist (i.e., KN38-7271) to investigate its effects on cerebral injury and its outcome (96). A total of 97 patients received KN38-7271 (1000 and 500 μg) or placebo within 4.5 h after the injury. Then, ICP and cerebral perfusion pressure (CPP) were analyzed from the start of treatment to the end of the 7th day. In addition, the pharmacokinetic efficacy of the drug was measured by survival and neurological improvement or deterioration on the 7th, 14th, 1st, and 3rd days, as well as 6 months after the injury.

The results showed that survival rates were significantly higher in the treatment group within 1 month after the injury, although this effect was not present after 6 months. Furthermore, critical ICP and CPP were less severe and less frequent in treated patients. No severe adverse effects were observed in the patients probably due to CB1/CB2 receptor agonists. These findings revealed that KN38-7271 was safe and well-tolerated, improved early survival rates, and induced beneficial effects on ICP and CPP.

In a retrospective review of registered data, adult patients with TBI were investigated for toxicology screen for THC. Moreover, the relationship between the mortality rate after TBI and THC positive screen test was studied (97). The results showed that the mortality rate in the positive THC screen group was significantly decreased, compared to that in the negative THC screen group. After adjusting for differences between the study cohorts on logistic regression, it was observed that a positive THC screen was independently associated with a higher survival rate after TBI. Therefore, it was concluded that a positive THC screen is associated with a decreased mortality rate in adult patients suffering from TBI.

 

Dexanabinol

Preclinical Studies

The HU-211 is a synthetic nonpsychotropic cannabinoid (45) that act as a noncompetitive NMDA receptor antagonist (46) and have antioxidant (47), as well as anti-inflammatory properties (TNF-α blocking) (48, 98). The HU-211 has been used in preclinical studies in several cases. Shohami et al. (99) used HU-211 (25 mg/kg i.p.) in experimental TBI in rats. It was administrated immediately and 1, 2, or 3 h after the injury and the rats were evaluated 1, 24, and 48 h after TBI.

The administration of HU-211 1 and 2 h after the injury was shown to be very effective in improving motor function recovery, reducing BBB breakdown by more than fourfold, and attenuating cerebral edema. However, administration 3 h after the injury was less pronounced. In another study, HU-211 administration (5 mg/kg i.v) in a rat model of TBI, 4 or 6 h after the injury made a significant improvement in neurological severity score (NSS) (100). To evaluate the long-term effects of the drug, the administration was performed 1 h after the injury, and additional doses were given later. The evaluation of NSS for 30 days showed that a single dose of HU-211 given 1 h after the injury or repeated doses during this period improved the clinical outcome.

Furthermore, HU-211 treatment 1 h after the injury was shown to alleviate the impaired cognitive functions in rats based on their performance in the Morris water maze. These results indicated that a therapeutic window of 4 h for HU-211 after the brain injury even with a single dose results in ameliorating the impairment in both motor and cognitive functions. Cytokines are the members of endogenous proteins, which are released by the cells of the immune system and affect the function of local and distant cells.

Interleukin-1 (IL-1), IL-6, and TNF-α have been identified in the brain in several pathological conditions, including various neurological diseases. In a study carried out by Shohami et al. (98), an experimental brain injury model was applied, and the induction of IL-1x, IL-1b, TNF-α, and IL-6 gene mRNA transcription, as well as TNF-α and IL-6 activity,  was performed to investigate the effects of HU-211 on TNF-α activity and neuronal protection. The results showed that HU-211 significantly inhibited TNF-α production at a posttranscriptional stage and improved the outcome of brain injury. As initial insult in TBI is followed by the secondary degeneration and failure of the CNS, damage to the optic nerve can lead to the axonal degeneration followed by a loss of retinal ganglion cells.

In a study conducted by M. Zalish et al. (101), long-term effects of HU-211 were investigated on the calibrated crush injury of the rat optic nerve. Treatment with a single intraperitoneal injection of HU-211 (7 mg/kg) began immediately after the injury. Transmission electron microscopic analysis of the excised optic nerves 30 days after the treatment showed that in HU-211 treated rats, the site of injury was traversed by unmyelinated and thinly myelinated axons that could be indicative of regenerative growth. Viable axons were detected in more than three-quarter of HU-211 treated rats. These results revealed that HU-211 was able to prevent the secondary degeneration and promote the generation after the injury to CNS.

 

Clinical studies

In a phase 1 trial, rising doses of HU-211 were safe and well-tolerated in healthy volunteers (102). In a phase 2 study performed by Knoller et al. (103), HU-211 was used in patients with severe brain injury to study the effects. Drug administration was started within 6 h after the injury, and the clinical outcomes were assessed throughout a 6-month follow-up period. It was observed that HU-211 treatment was safe and well-tolerated in severe head injury and resulted in a significantly better intracranial/cerebral perfusion pressure control without jeopardizing blood pressure. Finally, in a phase 3 study, clinical trial HU-211 was safe with no side effects and not associated with hepatic, renal, or cardiac toxicity. However, the findings showed no indication of differential treatment effects on the control of intracranial pressure or quality of life between HU-211 and placebo in patients (104)

Discussion and Conclusion

The ECS possesses promising effects in the treatment of diverse TBI pathology through releasing endogenous ligands or changes in cannabinoid receptors activity. The roles that ECS play in TBI pathology are as follows: A) Characterizing ligands that target cannabinoid receptors, and B) Regulating the levels of enzymes and making changes in cannabinoid receptors as a consequence of TBI. As it was shown in some studies, the early activation of ECS resulted in better protective effects than late activation. Furthermore, the activation of CB1 and CB2 protected locomotor activity and cognitive function in preclinical studies.

The CB2 activation ameliorates inflammation and modulates immune system towards anti-inflammatory and healing state. The 2-AG showed to decrease inflammation, oxidation, and neuronal cell death via CB1 mediation. Some known neuroprotective agents, such as Leptin and minocycline, were shown that their protective effects were mediated by CB1 and CB2 activity. On the other hand, in clinical studies the activation of CB1 and CB2 resulted in improved early survival but not late survival. Moreover, some beneficial effects on ICP and CCP were observed in clinical studies. Finally, HU-211 was shown to be effective in decreasing inflammation and protect the motor and cognitive functions in preclinical studies. However, in clinical studies, HU-211 only revealed to be safe and well-tolerated.

One of the main limitations of the present review was no full access to the literature, and due to the inadequacy of abstracts, some studies were forcibly excluded. This problem may affect this narrative review in a harmful way that was not intended by the authors. There are many aspects of ECS that have not been examined. Clinical trials that studied ECS drugs were very limited and showed no statistically significant protective effect in TBI patients, except for a retrospective study that demonstrated a positive screen test for cannabinoid use in TBI patients associated with lower mortality rate. Nonetheless, these data cannot be replicated in a controlled setting. To date, HU-211 is the only cannabinoid that has been used in patients suffering from TBI; however, it could not produce long-term effects in clinical trials.

In conclusion, numerous preclinical studies suggest that the ECS has many targets for therapeutic agents that might help decrease TBI pathologic influences. However, further studies should be performed to thoroughly investigate these targets. Clinical trials still lack the proof for proven evidence in preclinical studies. Therefore, future studies as clinical trials should use a higher number of research subjects and explore more modifications of ECS targets to provide a better target for novel therapeutic agents.

Conflict of Interest

There is no conflict of interests to be declared.

References

1.     Bagalman E. Traumatic brain injury among veterans. Congressional Research Service, Library of Congress, New York, USA; 2011.

2.     Mazlan M. 43-Traumatic brain injury. In: Cifu DX, Lew HL, editors. Braddom's rehabilitation care: a clinical handbook. New York: Elsevier Health Sciences; 2018. P. 305-14.

3.     Menon DK, Schwab K, Wright DW, Maas AI. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil. 2010; 91(11):1637-40. PMID: 21044706 DOI: 10.1016/j.apmr.2010.05.017

4.     McConeghy KW, Hatton J, Hughes L, Cook AM. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs. 2012; 26(7):613-36. PMID: 22668124 DOI: 10.2165/11634020-000000000-00000

5.     Pearson WS, Ovalle F Jr, Faul M, Sasser SM. A review of traumatic brain injury trauma center visits meeting physiologic criteria from The American College of Surgeons Committee on Trauma/Centers for Disease Control and Prevention Field Triage Guidelines. Prehosp Emerg Care. 2012; 16(3):323-8. PMID: 22548387 DOI: 10.3109/10903127.2012.682701

6.     Thurman D, Guerrero J. Trends in hospitalization associated with traumatic brain injury. JAMA. 1999; 282(10):954-7. PMID: 10485680

7.     Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, et al. Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. Lancet Public Health. 2016; 1(2):e76-83. PMID: 29253420 DOI: 10.1016/S2468-2667(16)30017-2

8.     Frieden T, Houry D, Baldwin G. Traumatic brain injury in the United States: epidemiology and rehabilitation. Atlanta: CDC; 2015. P. 1-74.

9.     Winkler EA, Minter D, Yue JK, Manley GT. Cerebral edema in traumatic brain injury: pathophysiology and prospective therapeutic targets. Neurosurg Clin N Am. 2016; 27(4):473-88. PMID: 27637397 DOI: 10.1016/j.nec.2016.05.008

10. Stocchetti N, Maas AI. Traumatic intracranial hypertension. N Engl J Med. 2014; 370(22):2121-30. PMID: 24869722 DOI: 10.1056/NEJMra1208708

11. Fujikawa DG. The role of excitotoxic programmed necrosis in acute brain injury. Comput Struct Biotechnol J. 2015; 13:212-21. PMID: 25893083 DOI: 10.1016/j.csbj.2015.03.004

12. Brotfain E, Leibowitz A, Dar DE, Krausz MM, Shapira Y, Koyfman L, et al. Severe traumatic brain injury and controlled hemorrhage in rats: quest for the optimal mean arterial blood pressure after whole fresh donor blood resuscitation. Shock. 2012; 38(6):630-4. PMID: 23143053 DOI: 10.1097/SHK.0b013e318272d59f

13. Dennis AM, Haselkorn ML, Vagni VA, Garman RH, Janesko-Feldman K, Bayɩr H, et al. Hemorrhagic shock after experimental traumatic brain injury in mice: effect on neuronal death. J Neurotrauma. 2009; 26(6):889-99. PMID: 18781889 DOI: 10.1089/
neu.2008.0512

14. Exo JL, Shellington DK, Bayir H, Vagni VA, Janesco-Feldman K, Ma L, et al. Resuscitation of traumatic brain injury and hemorrhagic shock with polynitroxylated albumin, hextend, hypertonic saline, and lactated ringer's: effects on acute hemodynamics, survival, and neuronal death in mice. J Neurotrauma. 2009; 26(12):2403-8. PMID: 19691424 DOI: 10.1089/neu.2009.0980

15. Hemerka JN, Wu X, Dixon CE, Garman RH, Exo JL, Shellington DK, et al. Severe brief pressure-controlled hemorrhagic shock after traumatic brain injury exacerbates functional deficits and long-term neuropathological damage in mice. J Neurotrauma. 2012; 29(12):2192-208. PMID: 22738159 DOI: 10.1089/neu.2011.2303

16. McBride DW, Szu JI, Hale C, Hsu MS, Rodgers VG, Binder DK. Reduction of cerebral edema after traumatic brain injury using an osmotic transport device. J Neurotrauma. 2014; 31(23):1948-54. PMID: 24959845 DOI: 10.1089/neu.2014.3439

17. Kinoshita K. Traumatic brain injury: pathophysiology for neurocritical care. J Intensive Care. 2016; 4(1):29. PMID: 27123305 DOI: 10.1186/s40560-016-0138-3

18. Jha SK. Cerebral edema and its management. Med J Armed Forces India. 2003; 59(4):326-31. PMID: 27407555 DOI: 10.1016/S0377-1237(03)80147-8

19. Leibson CL, Brown AW, Hall Long K, Ransom JE, Mandrekar J, Osler TM, et al. Medical care costs associated with traumatic brain injury over the full spectrum of disease: a controlled population-based study. J Neurotrauma. 2012; 29(11):2038-49. PMID: 22414023 DOI: 10.1089/neu.2010.1713

20. Corrigan JD, Whiteneck G, Mellick D. Perceived needs following traumatic brain injury. J Head Trauma Rehabil. 2004; 19(3):205-16. PMID: 15247843

21. Chakraborty S, Skolnick BE, Alves WM, Marshall LF, Narayan RK. Chapter 5: traumatic brain injury. In: Skolnick BE, Alves WM, editors. Handbook
of neuroemergency clinical trials. 2nd ed. Massachusetts: Academic Press; 2018. P. 85-109.

22. Meyer MJ, Megyesi J, Meythaler J, Murie-Fernandez M, Aubut JA, Foley N, et al. Acute management of acquired brain injury part II: an evidence-based review of pharmacological interventions. Brain Inj. 2010; 24(5):706-21. PMID: 20376996

23. Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, et al. Surgical management of acute epidural hematomas. Neurosurgery. 2006; 58(3 Suppl):S7-15. PMID: 16710967

24. Sahuquillo J, Arikan F. Decompressive craniectomy for the treatment of refractory high intracranial pressure in traumatic brain injury. Cochrane Database Syst Rev. 2006; 1:CD003983. PMID: 16437469 DOI: 10.1002/14651858.CD003983.pub2

25. Mechoulam R, Gaoni Y. Recent advances in the chemistry of hashish. Fortschritte der Chemie Organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products/Progrès dans la Chimie des Substances Organiques Naturelles. Vienna: Springer; 1967. P. 175-213.

26. Schurman LD, Lichtman AH. Endocannabinoids: a promising impact for traumatic brain injury. Front Pharmacol. 2017; 8:69. PMID: 28261100 DOI: 10.3389/fphar.2017.00069

27. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003; 4(11):873-84. PMID: 14595399 DOI: 10.1038/nrn1247

28. Mackie K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. 2006; 46:
101-22. PMID: 16402900 DOI: 10.1146/annurev.
pharmtox.46.120604.141254

29. Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant - do they exist? Br J Pharmacol. 2010;160(3):523-9. PMID: 20590562 DOI: 10.1111/j.1476-5381.2010.00745.x

30. Wiley JL, Marusich JA, Huffman JW. Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sci. 2014; 97(1):55-63. PMID: 24071522 DOI: 10.1016/j.lfs.2013.09.011

31. Antoniou T, Juurlink DN. Synthetic cannabinoids. CMAJ. 2014; 186(3):210. PMID: 24101614 DOI: 10.1503/cmaj.130510

32. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992; 258(5090):1946-9. PMID: 1470919

33. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50(1):83-90. PMID: 7605349

34. Hillard CJ. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat. 2000; 61(1):3-18. PMID: 10785538

35. Siegel GJ. Basic neurochemistry: molecular, cellular and medical aspects. Philadelphia: Lippincott Williams & Wilkins; 1999.

36. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991; 11(2):563-83. PMID: 1992016

37. Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F. CB2 receptors in the brain: role in central immune function. Br J Pharmacol. 2008; 153(2):240-51. PMID: 18037916 DOI: 10.1038/sj.bjp.0707584

38. Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010; 160(3):467-79. PMID: 20590558 DOI: 10.1111/j.
1476-5381.2010.00729.x

39. Pacher P, Hasko G. Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning. Br J Pharmacol. 2008; 153(2):252-62. PMID: 18026124 DOI: 10.1038/
sj.bjp.0707582

40. Benito C, Tolon R, Pazos M, Nunez E, Castillo A, Romero J. Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol. 2008; 153(2):277-85. PMID: 17934510 DOI: 10.1038/sj.bjp.0707505

41. Ashton JC, Glass M. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodege-neration. Curr Neuropharmacol. 2007; 5(2):73-80. PMID: 18615177

42. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008; 7(5):438-55. PMID: 18446159 DOI: 10.1038/nrd2553

43. Lutz B. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharmacol. 2004; 68(9):1691-8. DOI: 10.1016/j.bcp.2004.07.007

44. Bahr BA, Karanian DA, Makanji SS, Makriyannis A. Targeting the endocannabinoid system in treating brain disorders. Expert Opin Investig Drugs.
2006; 15(4):351-65.
PMID: 16548785 DOI: 10.1517/13543784.15.4.351

45. Mechoulam R, Feigenbaum JJ, Lander N, Segal M, Järbe TU, Hiltunen AJ, et al. Enantiomeric cannabinoids: stereospecificity of psychotropic activity. Experientia. 1988; 44(9):762-4. PMID: 3416993

46. Feigenbaum JJ, Bergmann F, Richmond SA, Mechoulam R, Nadler V, Kloog Y, et al. Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proc Natl Acad Sci. 1989; 86(23):9584-7. PMID: 2556719

47. Eshhar N, Striem S, Kohen R, Tirosh O, Biegon A. Neuroprotective and antioxidant activities of HU-211, a novel NMDA receptor antagonist. Eur J Pharmacol. 1995; 283(1-3):19-29. PMID: 7498309

48. Gallily R, Yamin A, Waksmann Y, Ovadia H, Weidenfeld J, Bar-Joseph A, et al. Protection against septic shock and suppression of tumor necrosis factor α and nitric oxide production by dexanabinol (HU-211), a nonpsychotropic cannabinoid. J Pharmacol Exp Ther. 1997; 283(2):918-24. PMID: 9353414

49. Biegon A, Joseph AB. Development of HU-211 as a neuroprotectant for ischemic brain damage. Neurol Res. 1995; 17(4):275-80. PMID: 7477742

50. Belayev L, Busto R, Zhao W, Ginsberg MD. HU-211,
a novel noncompetitive N-methyl-D-aspartate antagonist, improves neurological deficit and reduces infarct volume after reversible focal cerebral ischemia in the rat. Stroke. 1995; 26(12):2313-9.
PMID: 7491657

51. Mazzeo AT, Brophy GM, Gilman CB, Alves ÓL, Robles JR, Hayes RL, et al. Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. J Neurotrauma. 2009; 26(12):2195-206. PMID: 19621985 DOI: 10.1089/neu.2009.1012

52. Tapia-Perez JH, Sanchez-Aguilar M, Torres-Corzo JG, Gordillo-Moscoso A, Martinez-Perez P, Madeville P, et al. Effect of rosuvastatin on amnesia and disorientation after traumatic brain injury (NCT00329758). J Neurotrauma. 2008; 25(8):1011-7. PMID: 18690806 DOI: 10.1089/neu.2008.0554

53. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol. 2007; 6(1):29-38. PMID: 17166799 DOI: 10.1016/S1474-4422(06)70630-5

54. Amenta PS, Jallo JI, Tuma RF, Hooper DC, Elliott MB. Cannabinoid receptor type-2 stimulation, blockade, and deletion alter the vascular inflammatory responses to traumatic brain injury. J Neuroinflammation. 2014; 11:191. PMID: 25416141 DOI: 10.1186/s12974-014-0191-6

55. Gallily R, Breuer A, Mechoulam R. 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice. Eur J Pharmacol. 2000; 406(1):R5-7. PMID: 11011050

56. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 2001; 413(6855):527-31. PMID: 11586361 DOI: 10.1038/35097089

57. Amenta PS, Jallo JI, Tuma RF, Elliott MB. A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J Neurosci Res. 2012; 90(12):2293-305. PMID: 22903455 DOI: 10.1002/jnr.23114

58. Elliott MB, Tuma RF, Amenta PS, Barbe MF, Jallo JI. Acute effects of a selective cannabinoid-2 receptor agonist on neuroinflammation in a model of traumatic brain injury. J Neurotrauma. 2011; 28(6):973-81. PMID: 21332427 DOI: 10.1089/neu.2010.1672

59. Dikmen SS, Corrigan JD, Levin HS, Machamer J, Stiers W, Weisskopf MG. Cognitive outcome following traumatic brain injury. J Head Trauma Rehabil. 2009; 24(6):430-8. PMID: 19940676 DOI: 10.1097/HTR.
0b013e3181c133e9

60. Arain M, Khan M, Craig L, Nakanishi ST. Cannabinoid agonist rescues learning and memory after a traumatic brain injury. Ann Clin Transl Neurol. 2015; 2(3):289-94. PMID: 25815355 DOI: 10.1002/acn3.163

61. Baek JH, Darlington CL, Smith PF, Ashton JC. Antibody testing for brain immunohistochemistry: brain immunolabeling for the cannabinoid CB2 receptor.
J Neurosci Methods. 2013; 216(2):87-95. PMID: 23583232 DOI: 10.1016/j.jneumeth.2013.03.021

62. Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010; 58(9):1017-30. PMID: 20468046 DOI: 10.1002/glia.20983

63. Benito C, Núñez E, Tolón RM, Carrier EJ, Rábano A, Hillard CJ, et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J Neurosci. 2003; 23(35):11136-41. PMID: 14657172

64. Donat CK, Fischer F, Walter B, Deuther-Conrad W, Brodhun M, Bauer R, et al. Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet. Acta Neurobiol Exp (Wars). 2014; 74(2):197-210. PMID: 24993629

65. Schomberg D, Olson JK. Immune responses of microglia in the spinal cord: contribution to pain states. Exp Neurol. 2012; 234(2):262-70. PMID: 22226600 DOI: 10.1016/j.expneurol.2011.12.021

66. 66. Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014; 11(1):98. PMID: 24889886 DOI: 10.1186/1742-2094-11-98

67. Braun M, Khan ZT, Khan MB, Kumar M, Ward A, Achyut BR, et al. Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization. Brain Behav Immun. 2018; 68:224-37. PMID: 29079445 DOI: 10.1016/j.bbi.2017.10.021

68. Reiner A, Heldt SA, Presley CS, Guley NH, Elberger AJ, Deng Y, et al. Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int J Mol Sci. 2014; 16(1):758-87. PMID: 25561230 DOI: 10.3390/ijms16010758

69. Bu W, Ren H, Deng Y, Del Mar N, Guley NM, Moore BM, et al. Mild traumatic brain injury produces neuron loss that can be rescued by modulating microglial activation using a CB2 receptor inverse agonist. Front Neurosci. 2016; 10:449. PMID: 27766068 DOI: 10.3389/fnins.2016.00449

70. Sigurdsson T, Duvarci S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Front Syst Neurosci. 2016; 9:190. PMID: 26858612 DOI: 10.3389/fnsys.2015.00190

71. Spellman T, Rigotti M, Ahmari SE, Fusi S, Gogos JA, Gordon JA. Hippocampal-prefrontal input supports spatial encoding in working memory. Nature. 2015; 522(7556):309-14. PMID: 26053122 DOI: 10.1038/
nature14445

72. Bähner F, Demanuele C, Schweiger J, Gerchen MF, Zamoscik V, Ueltzhöffer K, et al. Hippocampal-dorsolateral prefrontal coupling as a species-conserved cognitive mechanism: a human translational imaging study. Neuropsychopha-rmacology. 2015; 40(7):1674-81. PMID: 25578799 DOI: 10.1038/npp.2015.13

73. Zelikowsky M, Hersman S, Chawla MK, Barnes CA, Fanselow MS. Neuronal ensembles in amygdala, hippocampus, and prefrontal cortex track differential components of contextual fear. J Neurosci. 2014; 34(25):8462-6. PMID: 24948801 DOI: 10.1523/
JNEUROSCI.3624-13.2014

74. Mueller EM, Panitz C, Hermann C, Pizzagalli DA. Prefrontal oscillations during recall of conditioned and extinguished fear in humans. J Neurosci.
2014; 34(21):7059-66. PMID: 24849342 DOI: 10.1523/JNEUROSCI.3427-13.2014

75. Bocchio M, Capogna M. Oscillatory substrates of
fear and safety. Neuron. 2014; 83(4):753-5.
PMID: 25144870 DOI: 10.1016/j.neuron.2014.08.014

76. Maroun M. Medial prefrontal cortex: multiple roles in fear and extinction. Neuroscientist. 2013; 19(4):370-83. PMID: 23090707 DOI: 10.1177/107385841
2464527

77. Popa D, Duvarci S, Popescu AT, Léna C, Paré D. Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep. Proc Natl Acad Sci U S A. 2010; 107(14):6516-9. PMID: 20332204 DOI: 10.1073/pnas.0913016107

78. Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010; 30(48):16082-90. PMID: 21123555 DOI: 10.1523/JNEUROSCI.1731-10.2010

79. SierraMercado D Jr, Corcoran KA, LebrónMilad K, Quirk GJ. Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction. Eur J Neurosci. 2006; 24(6):1751-8. PMID: 17004939 DOI: 10.1111/j.1460-9568.2006.05014.x

80. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol Psychiatry. 2006; 60(4):376-82. PMID: 16919525 DOI: 10.1016/j.biopsych.2006.06.004

81. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013; 14(9):609-25. PMID: 23942470 DOI: 10.1038/nrn3381

82. Liu Y, McAfee SS, Guley NM, Del Mar N, Bu W, Heldt SA, et al. Abnormalities in dynamic brain activity caused by mild traumatic brain injury are partially rescued by the cannabinoid type-2 receptor inverse agonist SMM-189. eNeuro. 2017; 4(4):387. PMID: 28828401 DOI: 10.1523/ENEURO.0387-16.2017

83. Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 2009; 373(9669):1105-10. PMID: 19233461 DOI: 10.1016/S0140-6736(09)60214-2

84. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003; 4(11):873-84. PMID: 14595399 DOI: 10.1038/nrn1247

85. Wang X, Wang Y, Zhang C, Liu C, Yang HF, Hu WH, et al. Endogenous cannabinoid system alterations and their role in epileptogenesis after brain injury in rat. Epilepsy Res. 2016; 128:35-42. PMID: 27810514 DOI: 10.1016/j.eplepsyres.2016.10.002

86. Lopez-Rodriguez AB, Mela V, Acaz-Fonseca E, Garcia-Segura LM, Viveros MP. CB2 cannabinoid receptor is involved in the anti-inflammatory effects of leptin in a model of traumatic brain injury. Exp Neurol. 2016; 279:274-82. PMID: 27006282 DOI: 10.1016/j.expneurol.2016.03.018

87. Siopi E, Llufriu-Dabén G, Fanucchi F, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M. Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: the effect of minocycline. Neurosci Lett. 2012; 511(2):110-5. PMID: 22314279 DOI: 10.1016/j.neulet.2012.
01.051

88. Siopi E, Cho AH, Homsi S, Croci N, Plotkine M, Marchand-Leroux C, et al. Minocycline restores sAPPα levels and reduces the late histopathological consequences of traumatic brain injury in mice.
J Neurotrauma. 2011; 28(10):2135-43. PMID: 21770756 DOI: 10.1089/neu.2010.1738

89. Siopi E, Calabria S, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M. Minocycline restores olfactory bulb volume and olfactory behavior after traumatic brain injury in mice. J Neurotrauma. 2012; 29(2):354-61. PMID: 21910642 DOI: 10.1089/neu.2011.2055

90. Homsi S, Federico F, Croci N, Palmier B, Plotkine M, Marchand-Leroux C, et al. Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice. Brain Res. 2009; 1291:122-32. PMID: 19631631 DOI: 10.1016/j.brainres.2009.07.031

91. Homsi S, Piaggio T, Croci N, Noble F, Plotkine M, Marchand-Leroux C, et al. Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve-week follow-up study. J Neurotrauma. 2010; 27(5):911-21. PMID: 20166806 DOI: 10.1089/neu.2009.1223

92. Tikka T, Fiebich BL, Goldsteins G, Keinänen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001; 21(8):2580-8. PMID: 11306611

93. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001; 166(12):7527-33. PMID: 11390507

94. Markovic D, Vinnakota K, Van Rooijen N, Kiwit J, Synowitz M, Glass R, et al. Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression. Brain Behav Immun. 2011; 25(4):624-8. PMID: 21324352 DOI: 10.1016/j.bbi.2011.01.015

95. Lopez-Rodriguez AB, Siopi E, Finn DP, Marchand-Leroux C, Garcia-Segura LM, Jafarian-Tehrani M, et al. CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice. Cereb Cortex. 2013; 25(1):35-45. PMID: 23960212 DOI: 10.1093/cercor/bht202

96. Firsching R, Piek J, Skalej M, Rohde V, Schmidt U, Striggow F, et al. Early survival of comatose patients after severe traumatic brain injury with the dual cannabinoid CB1/CB2 receptor agonist KN38-7271: a randomized, double-blind, placebo-controlled phase II trial. J Neurol Surg A Cent Eur Neurosurg. 2012; 73(4):204-16. PMID: 22696266 DOI: 10.1055/s-0032-1304815

97. Nguyen BM, Kim D, Bricker S, Bongard F, Neville A, Putnam B, et al. Effect of marijuana use on outcomes in traumatic brain injury. Am Surg. 2014; 80(10):979-83. PMID: 25264643

98. Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant. J Neuroimmunol. 1997; 72(2):169-77. PMID: 9042110

99. Shohami E, Novikov M, Mechoulam R. A nonpsychotropic cannabinoid, HU-211, has cerebroprotective effects after closed head injury in the rat. J Neurotrauma. 1993; 10(2):109-19. PMID: 8411215 DOI: 10.1089/neu.1993.10.109

100.       Shohami E, Novikov M, Bass R. Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Res. 1995; 674(1):55-62. PMID: 7773695

101.       Zalish M, Lavie V. Dexanabinol (HU-211) has a beneficial effect on axonal sprouting and survival after rat optic nerve crush injury. Vision Res. 2003; 43(3):237-42. PMID: 12535983

102.       Brewster ME, Pop E, Foltz RL, Reuschel S, Griffith W, Amselem S, et al. Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers. Int J Clin Pharmacol Ther. 1997; 35(9):361-5. PMID: 9314087

103.       Knoller N, Levi L, Shoshan I, Reichenthal E, Razon N, Rappaport ZH, et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med. 2002; 30(3):548-54. PMID: 11990913

104.       Maas AI, Murray G, Henney H 3rd, Kassem N, Legrand V, Mangelus M, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006; 5(1):38-45. PMID: 16361021 DOI: 10.1016/S1474-4422(05)70253-2

 

 

Type of Study: Review | Subject: Neurosurgery
Received: 2018/08/29 | Accepted: 2019/02/19 | ePublished ahead of print: 2019/04/27 | Published: 2019/06/12 | ePublished: 2019/06/12

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Journal of Surgery and Trauma

Designed & Developed by : Yektaweb