Targeting the endocannabinoid system in treating brain disorders

Abstract

Recent cannabinoid research has a primary focus on developing therapeutics against human diseases. Many studies on cannabinoids indicate important progress for protection against several neurodegenerative disorders. Agonists of cannabinoid receptors activate signalling pathways in the brain that are linked to neuronal repair and cell maintenance, and endogenous ligands can also activate neuroprotective responses. These endocannabinoids are bioactive fatty acid amides and esters that are synthesised in the brain and include arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol. Endocannabinoids are released in response to pathogenic events, thus representing a potential compensatory repair mechanism. Enhancing this on-demand action of endocannabinoids is a strategy with which to promote endogenous repair signalling. For such enhancement, considerable work has gone into modulating the availability of endocannabinoids by blocking the processes of their deactivation. The targets include the anandamide-hydrolysing enzyme fatty acid amide hydrolase, the carrier-mediated anandamide transport system and 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase. The activity of endocannabinoids is terminated through transport and degradation and, accordingly, selective inhibitors of these processes effectively exploit the protective nature of cannabinergic responses. This review highlights recent studies implicating the endocannabinoid system in neuroprotection against different disorders of the CNS.

Endocannabinoid Enhancement Protects against Kainic Acid-Induced Seizures and Associated Brain Damage

“…Note that although FAAH knockout mice were found to exhibit susceptibility to spastic and proconvulsant activity (Cravatt et al, 2001;Clement et al, 2003), dosing with the potent AM374 compound facilitated a controlled modulation of FAAH to promote protective cannabinergic signals. In relation to the present results, inhibiting endocannabinoid transport has been shown to reduce motor hyperactivity and seizure severity (Lastres-Becker et al, 2002;Marsicano et al, 2003), and several types of neuroprotection have been described with agonists that activate CB1 responses (see Bahr et al, 2006). When endocannabinoid signaling is disrupted through genetic or pharmacological means, the resultant proconvulsant conditions can lead to neuronal compromise (Wallace et al, 2002(Wallace et al, , 2003Marsicano et al, 2003;Monory et al, 2006).…”

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…AM6701 afforded greater protection against the excitotoxic events than AM6702, an inhibitor more potent toward FAAH than MAGL. Blocking endocannabinoid deactivation mechanisms represents an exploitable avenue for reducing excitotoxic damage through dual targeting of pharmacotherapeutic pathways [13,[45][46][47][48]. Blocking the inactivation of endocannabinoid responses is 1 such strategy to promote protective signaling after pathological injury and ameliorate cellular disturbances associated with excitotoxicity.…”

“…CB1 receptor activation by endocannabinoids is important for cell viability, and disruption of such signals has been found to prevent neuronal maintenance and to increase excitotoxic vulnerability [45]. A propensity for the receptor activation may be part of repair responses as previous studies have demonstrated elevated endocannabinoid levels in the brain of animals injected with an excitotoxin [14,[31][32][33].…”

“…According to Long et al [66], dual augmentation of the AEA and 2-AG signaling pathways allows these 2 lipid transmitters to engage in extensive crosstalk. A critical balance between AEA and 2-AG levels, controlled by endocannabinoid synthesizing and metabolizing enzymes, may therefore be important for normal physiological processes, as well as to promote repair after pathological events [1,45,48,67]. Dual FAAH/MAGL inhibitors may thus be more viable as neuroprotectants against excitotoxic brain injury.…”

Expression of Cannabinoid CB1 Receptors in Models of Diabetic Neuropathy

“…Much of the research thus far has focused on the protective role of cannabinoids in the central nervous system in response to chronic neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis, or injury associated with stroke or brain trauma (reviewed by Bahr et al, 2006). The exact mechanisms involved in their neuroprotectant effects remain unclear but involve both CB 1 receptor-independent (antioxidant) and -dependent mechanisms (inhibition of Ca 2ϩ influx, reduced glutamate release and excitotoxicity, vasodilatation, increased NGF production and neurotrophic support, and hypothermia).…”