The dual neuroprotective–neurotoxic profile of cannabinoid drugs

Abstract

Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/ neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of D 9 -tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre-or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed. LINKED ARTICLESThis article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2011.163.issue-7 Abbreviations 2AG, 2-arachidonylglycerol; BAY 38-7271, [(-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate]; CBs, cannabinoids, the psychoactive ingredients of the cannabis plant, their synthetic analogues and the endogenous ligands that act through CB1 and/or CB2 receptors. This definition excludes, within the framework of the present review, the non-psychoactive ingredients of cannabis such as cannabidiol; CO, carbon monoxide; CP 55 940 [(-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol)]; ERK, extracellular signal-regulated kinase; HU-210 ((-)-11-hydroxy-D 8 -tetrahydrocannabinol-dimethylheptyl); i.p., intraperitoneal; i.v., intravenous; JNK, c-Jun N-terminal kinase; NO, nitric oxide; PTZ, pentylenetetrazole; Raf1, murine leukaemia viral oncogene homolog 1; THC, D 9 -tetrahydrocannabinol; TNFa, tumour necrosis factor a; WIN 55,212-2 [(R)-(+)-(2,3-fihydro-5-methyl-3-[(morphonolinyl)methyl]pyrrolol[1,2,3-del]-1,4-benzoxazin-yl)(1-naphtaleneyl)methanone mesylate]; WIN 55, voltage-gated calcium channels (Howlett, 1995;Pertwee, 1997;Howlett et al., 2010). Gi/o proteins also mediate the effect of CBs on the mitogen-a...

High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

“…The hypoxic-ischemic insult in our model produces more severe multiorgan damage compared to these studies [2,3,4,5]. As the effects of cannabinoids have been shown to depend both on the dose and pathophysiological setting [11,12], we hypothesized that higher doses of CBD could be required to demonstrate efficacy in this animal model.…”

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

“…Previous animal studies have already demonstrated hepatoprotective effects of various cannabinoid drugs [6,7,8,9,10,11,12,25,26]. It should be noted, however, that these studies presented a common experimental features: the doses that were administrated intraperitonealy ranged between 3 and 20 mg/kg (the doses that also induce the conventional acute effects of cannabinoids).…”

“…Oxidative stress and inflammatory stimuli may trigger hepatic endocannabinoid production [6]. The protective effect of various cannabinoid agonists has previously been demonstrated in a well characterized mouse model of hepatic I/R injury [6,7,8,9,10,11,12]. All these cannabinoids has been applied at high doses (3-20 mg/kg) that also induce the conventional pharmacological effects of cannabinoids.…”

“…administration of Δ9- tetrahydrocannabiol (THC), the major psychoactive ingredient of marijuana, at an extremely low dose (0.002 mg/kg, which is 3-4orders of magnitude lower than doses that evoke the conventional acute effects of the drug), protected the mice and prevented the development of long-term cognitive deficits induced by the epileptogenic drug pentylenetetrazole, by pentobarbital deep anesthesia or by CO intoxication [10,11,12]. In addition we have demonstrated that a single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage [13].…”

Attentional dysfunction in abstinent long-term cannabis users with and without schizophrenia

“…However, as no healthy cannabis users were included as a control group, it remains unclear whether this effect of cannabis was specific for schizophrenic patients. Interestingly, several studies in experimental animals showed that cannabinoids may have opposing effects depending on whether the animals were concomitantly treated with neurotoxic agents, i.e., cannabinoids were toxic when given alone, but neuroprotective when given in combination with other neurotoxic agents [77][78][79][80]. Taken together, there is some evidence to suggest that cannabinoids may have negative effects on certain neuropsychological functions, but may also be associated with beneficial effects in cases where (specific) brain dysfunctions already exist.…”