The role of endocannabinoid pathway in the neuropathology of Alzheimer's disease: Can the inhibitors of MAGL and FAAH prove to be potential therapeutic targets against the cognitive impairment associated with Alzheimer's disease?
Alzheimer's disease is a neurodegenerative disease characterized by progressive decline of cognitive function in combination with neuronal death. Current approved treatment target single dysregulated pathway instead of multiple mechanism, resulting in lack of efficacy in slowing down disease progression. The proclivity of endocannabinoid system to exert neuroprotective action and mitigate symptoms of neurodegeneration condition has received substantial interest. Growing evidence suggest the endocannabinoids (eCB) system, viz. anadamide (AEA) and arachidonoyl glycerol (2-AG), as potential therapeutic targets with the ability to modify Alzheimer's pathology by targeting the inflammatory, neurodegenerative and cognitive aspects of the disease. In order to modulate endocannabinoid system, number of agents have been reported amongst which are inhibitors of the monoacylglycerol (MAGL) and fatty acid amide hydrolase (FAAH), the enzymes that hydrolyses 2-AG and AEA respectively. However, little is known regarding the exact mechanistic signalling and their effects on pathophysiology and cognitive decline associated with Alzheimer's disease. Both MAGL and FAAH inhibitors possess fascinating properties that may offer a multi-faceted approach for the treatment of Alzheimer's disease such as potential to protect neurons from deleterious effect of amyloid-β, reducing phosphorylation of tau, reducing amyloid-β induced oxidative stress, stimulating neurotrophin to support brain intrinsic repair mechanism etc. Based on empirical evidence, MAGL and FAAH inhibitors might have potential for therapeutic efficacy against cognitive impairment associated with Alzheimer's disease. The aim of this review is to summarize the experimental studies demonstrating the polyvalent properties of MAGL or FAAH inhibitor compounds for the treatment of Alzheimer's disease, and also effect of these on learning and types of memories, which together encourage to study these compounds over other therapeutics targets. Further research in this direction would enhance the molecular mechanisms and development of applicable interventions for the treatment of Alzheimer's disease, which nevertheless stay as the primary unmet need.
Bajaj S
，Jain S
，Vyas P
，Bawa S
，Vohora D
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The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceral pain models in Rodents.
Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models.
Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing.
PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR).
The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain.
Sakin YS
，Dogrul A
，Ilkaya F
，Seyrek M
，Ulas UH
，Gulsen M
，Bagci S
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