Effect of the MAGL/FAAH Dual Inhibitor JZL-195 on Streptozotocin-Induced Alzheimer’s Disease-like Sporadic Dementia in Mice with an Emphasis on Aβ, HSP-70, Neuroinflammation, and Oxidative Stress

Abstract

Alzheimer's disease is identified by pathological hallmarks such as intracellular neurofibrillary tangles (NFTs) and extracellular amyloid β plaques. Several hypotheses exist to define the neurodegeneration including microglial activation associated with neuroinflammatory processes. Recently, pharmacological inhibition of endocannabinoid (eCB)-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), is being investigated to modulate the pathology of Alzheimer's disease. While MAGL inhibitors upregulate 2-acyl glycerol (2-AG) levels and reduce neuroinflammation, FAAH inhibitors elevate anandamide (AEA) levels and prevent the degradation of HSP-70, thereby preventing the phosphorylation of tau protein and formation of NFTs in neural cells. We investigated the possible neuroprotective potential of the dual MAGL/FAAH inhibitor JZL-195 (20 mg/kg) against ICV-STZ-induced sporadic Alzheimer's disease (SAD) in Swiss albino mice using donepezil (5 mg/kg) as the standard. The protective effects of JZL-195 were observed by the reversal of altered levels of Aβ 1−42 , HSP-70, neuroinflammatory cytokines, and oxidative stress markers. However, JZL-195 expressed no cognitive improvement when assessed by spontaneous alternation behavior and Morris water maze tests and no effects on the AChE enzyme level in the hippocampal tissues of mice. Therefore, the findings of the present study indicate that although JZL-195 exhibited no improvement in cognitive deficits associated with sporadic Alzheimer's disease, it displayed significant reversal of the biochemical anomalies, thereby suggesting its therapeutic potential against the sporadic Alzheimer's disease model.

Positive association between plasmatic levels of orexin A and the endocannabinoid-derived 2-arachidonoyl lysophosphatidic acid in Alzheimer’s disease

“…Several investigators have demonstrated that 2-AG can be metabolized to 2-arachidonoyl LPA (herein named 2-AGP), a selective ligand of LPA1R ( Kanoh et al, 1986 ; Shim et al, 1989 ; Nakane et al, 2002 ), which modulates synaptic plasticity, Tau phosphorylation and cognitive function ( Castilla-Ortega et al, 2011 ; Roza et al, 2019 ). Our data report elevation of 2-AGP in CSF and plasma of AD patients in agreement with recent findings that indicate the failure of cognitive improvement after JZL-195 pharmacological inhibition of MAGL and FAAH activities in mouse model of AD ( Bajaj et al, 2022 ).…”

Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank

“…For example, we observe that putatively damaging bi-allelic variation in FAAH, a fatty acid amide hydrolase 37 , are associated with increased risk of dementia (log 10 (OR) = 22.92 (12.35−33.48), 𝑃 = 1.06×10 −5 ), consequently offering evidence supporting the hypothesis that lipid metabolism dysfunction is central to dementia pathogenesis 38 .…”

Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?

“…156 In contrast, inhibitors of endocannabinoid synthesis reduced amyloid-β load and neuroinflammation but failed to improve cognition. 157 In the clinic, ligands of Cannabinoid receptors are currently tested as neuromodulators to influence the behavioral and psychological symptoms in subjects with AD (NCT02351882). Additionally, gene therapy with recombinant BDNF is currently assessed in a phase 1 trial including people affected with AD and mild cognitive impairment to reduce neurodegeneration and rebuild synapses (NCT05040217).…”

“…In preclinical models of AD, recombinant BDNF infusion reverted cognitive decline without altering the amyloid-β load (151). In contrast, inhibitors of endocannabinoid synthesis reduced amyloid-β load and neuroinflammation but failed to improve cognition (152). In the clinic, ligands of Cannabinoid receptors are currently tested as neuromodulators to influence the behavioral and psychological symptoms in subjects with AD (NCT02351882).…”