Δ⁹‐Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors

Abstract

Background and purpose: It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage. In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB 1 ) agonist, D 9 -tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil. Experimental approach: The effects of AM 404 (0.015-2 mg kg À1 ) and THC (0.05-2 mg kg À1 ), given 5 min after ischaemia, were measured from 1 h to 7 days in terms of electroencephalographic (EEG) total spectral power, spontaneous motor activity, memory function, rectal temperature and hippocampal CA 1 neuronal count. Key results: Over the dose range tested, AM 404 (2 mg kg À1 ) and THC (1 mg kg À1 ) completely reversed the ischaemiainduced behavioural, EEG and histological damage. Only THC (1 and 2 mg kg À1 ) induced a decrease of body temperature. Pretreatment with the selective CB 1 receptor antagonist, AM 251 (1 mg kg À1 ) and the opioid antagonist, naloxone (2 mg kg À1 ) reversed the protective effect induced by both AM 404 and THC while the TRPV 1 vanilloid antagonist, capsazepine (0.01 mg kg À1 ), was ineffective. Conclusions and implications: Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB 1 and opioid receptors. Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies.

Cannabinoids and Epilepsy

“…Δ9-THC exerts potent anti-inflammatory functions via CB 1 Rs and CB 2 Rs on microglia, the primary immune cells in the CNS. Δ9-THC or CB 1 R agonists limit neurotoxicity in in vitro and in vivo assays, including chemotoxic [80][81][82][83], low Mg 2+ [84], and ischemic [85,86] models. Δ9-THC has antioxidant effects in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-and N-methyl-D-aspartate-mediated cytotoxicity models via a CB 1 R-independent mechanism [87].…”

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

“…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].…”

“…Most of these studies were conducted with the cannabinoid administered at least after the cytotoxic insult [12-19, 21-26, 28-35]. In most cases, the benefits obtained with these cannabinoid-related compounds (e.g., improved neurological performance, reduced infarct size, edema, BBB disruption, inflammation and gliosis, and control of immunomodulatory responses) involved the activation of CB 1 R (e.g., HU-210 [12], WIN55,212-2 [13,14], TAK-937 [15,16], BAY 38-7271 [17,18], Δ 9 -THC [19], and PEA [36]) and/or CB 2 R (e.g., AraS [29], O-3853, O-1966, and JWH-133 [30][31][32][33][34][35] mice with a genetic deficiency in CB 1 R or, to a lesser extent, CB 2 R. For example, CB 1 -/-mice showed increased infarct size and neurological deficits after tMCAO, concomitant with a reduction in cerebral blood flow and NMDA excitotoxicity [37], and a similar greater vulnerability was also found in TBI models [24], then supporting the protective role of CB 1 R against both pathological conditions. In the case of CB 2 -/-mice, results were controversial, with a study reporting larger cerebral infarction and a worsened neurological function after tMCAO [30], but others describing no differences using permanent MCAO [32,33], despite the notable effects found in pharmacological experiments with compounds selectively activating the CB 2 R [30][31][32][33][34][35].…”

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

“…In addition, CB1 knock-out mice [122] show increased mortality from permanent focal cerebral ischemia and larger infarcts after transient focal cerebral ischemia, compared with the wild-type mice. On the other hand, other studies were focused on the possible neuroprotective effect of diverse cannabinoid-related compounds after ischemia, such as endocannabinoids [123][124][125] , antagonists such as rimonabant [126] , and compounds that inhibit the degradation of them [127,128] .…”