Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia

Lavie, Gil; Teichner, Angella; Shohami, Esther; Ovadia, Haim; Leker, Ronen R.

doi:10.1016/s0006-8993(01)02356-3

Cited by 39 publications

(25 citation statements)

References 21 publications

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“…A similar long therapeutic time window in brain ischemia has been reported for other pharmacological strategies aimed at reducing post-ischemic inflammation (Iadecola et al, 1995;Nagayama et al, 1998;Cash et al, 2001). In addition, several studies have found neuroprotective effects of different compounds when administered after ischemia (Jiang et al, 1998;Yrjanheikki et al, 1999;Haag et al, 2000;Phillips et al, 2000;Zhang et al, 2001;Snider et al, 2001;Lavie et al, 2001;Mary et al, 2001), suggesting that brain injury produced by cerebral ischemia develops over a period of hours to days after the primary event.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Candelario‐Jalil

Alvarez

González-Falcón

et al. 2002

European Journal of Pharmacology

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Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils.Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 minutes before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34 ± 9 % protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Candelario‐Jalil

Alvarez

González-Falcón

et al. 2002

European Journal of Pharmacology

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“…In the case of TBI, damage is most commonly caused either by closed (concussion) or open head injury (stab wound). The cannabinoids having beneficial effects in these models included 1) dexanabinol (HU-211) [8][9][10][11], which is a synthetic compound having a chemical structure of a classic cannabinoid but no activity at cannabinoid receptors; 2) nonselective synthetic cannabinoid agonists such as HU-210, the active enantiomer of HU-211 [12], WIN 55,212-2 [13,14], TAK-937 [15,16], and BAY 38-7271 [17,18]; 3) phytocannabinoids such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) [19], which binds not only CB 1 R and CB 2 R, but also cannabidiol (CBD), which has no affinity at these receptors but was highly active against brain ischemia [20][21][22]; 4) endocannabinoids such as 2-arachidonoylglycerol (2-AG), in particular in TBI induced by closed head injury [23][24][25], but also in experimental ischemia [26], and also anandamide [27] and its related signaling lipids palmitoylethanolamide (PEA) [28], oleoylethanolamide [27], and N-arachidonoyl-L-serine (AraS) [29]; and 5) selective CB 2 R targeting ligands such as O-3853, O-1966, and JWH-133 [30][31][32][33][34][35]. Most of these studies were conducted with the cannabinoid administered at least after the cytotoxic insult [12-19, 21-26, 28-35].…”

Section: Cannabinoids and Acute Brain Damage: Stroke And Brain Traumamentioning

confidence: 99%

“…In addition, their strong anti-inflammatory profile appears to be one of the most consistent mechanisms leading to reduction of the lesion, by actions affecting resident, vascular, and peripheral cells. It is also important to remark that the benefits of certain cannabinoids in acute stroke and TBI also involve effects on other pharmacological targets, such as the blockade of NMDA receptors (e.g., HU-211 [8][9][10][11]), the activation of 5-HT 1A receptors (e.g., CBD [20][21][22]), and the activation of transient receptor potential vanilloid-type 1 receptors (e.g., PEA [36] and AraS) [29]). It is also possible that part of these beneficial effects may be related to the hypothermic effects of cannabinoids, but it is well known that such effects are CB 1 R-mediated [12,38,39].…”

Section: Cannabinoids and Acute Brain Damage: Stroke And Brain Traumamentioning

confidence: 99%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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“…In addition, others have found that closed head injury (CHI) in mice causes strong enhancement of 2-AG production and that exogenous 2-AG administration after CHI in mice leads to significant reduction of brain edema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls [115]. In farct volumes of spontaneously hypertensive rats subjected to permanent middle cerebral artery occlusion were smaller in animals treated with dexanabinol [116]. In sum, it appears that the cannabinoid system is upregulated in response to various brain insults, perhaps representing an attempt to provide endogenous neuroprotective actions, and it is likely that therapeutic strategies based on modifying endocannabinoid activity will prove useful.…”

Section: Neuroprotectionmentioning

confidence: 99%

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

Grant

Cahn

2005

Clinical Neuroscience Research

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The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.

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Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia

Cited by 39 publications

References 21 publications

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

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