Acs Chem Neurosci
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Review
"Redundancy" of endocannabinoid inactivation: new challenges and opportunities for pain control.
Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB(1) and CB(2) receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. ⋯ Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of "dirty drugs", and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics.
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Fatty acid amide hydrolase (FAAH) plays the central role in the degradation of bioactive N-acylethanolamines such as the endocannabinoid arachidonoylethanolamide (anandamide) in brain and peripheral tissues. A lysosomal enzyme referred to as N-acylethanolamine-hydrolyzing acid amidase (NAAA) catalyzes the same reaction with preference to palmitoylethanolamide, an endogenous analgesic and neuroprotective substance, and is therefore expected as a potential target of therapeutic drugs. In the in vitro assays thus far performed, the maximal activity of NAAA was achieved in the presence of both nonionic detergent (Triton X-100 or Nonidet P-40) and the SH reagent dithiothreitol. ⋯ Even in the presence of phosphatidylcholine and dihydrolipoic acid, however, the preferential hydrolysis of palmitoylethanolamide was unaltered. We also investigated a possible compensatory induction of NAAA mRNA in brain and other tissues of FAAH-deficient mice. However, NAAA expression levels in all the tissues examined were not significantly altered from those in wild-type mice.
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Growing evidence suggests that on-pathway amyloid-β (Aβ) oligomers are primary neurotoxic species and have a direct correlation with the onset of Alzheimer's disease (AD). One promising therapeutic strategy to block AD progression is to reduce the levels of these neurotoxic Aβ species using small molecules. While several compounds have been shown to modulate Aβ aggregation, compounds with such activity combined with safety and high blood-brain barrier (BBB) permeability have yet to be reported. ⋯ Therefore, the two additional methyl groups of BBG and other structural differences between the congeners are important in the interaction of BBG with Aβ leading to formation of nontoxic Aβ aggregates. Our findings support the hypothesis that generating nontoxic aggregates using small molecule modulators is an effective strategy for reducing Aβ cytotoxicity. Furthermore, key structural features of BBG identified through structure-function studies can open new avenues into therapeutic design for combating AD.
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Aquaporin 4 (AQP4), the most abundant isozyme of the water specific membrane transporter aquaporin family, has now been implicated to play a significant role in the pathogenesis of various disease processes of the nervous system from epilepsy to Alzheimer's disease. Considering its clinical relevance, it is highly desirable to develop a noninvasive method for the quantitative analysis of AQP distribution in humans under clinical settings. ⋯ Here, we report the successful development of a PET ligand for AQP4 imaging based on TGN-020, a potent AQP4 inhibitor developed previously in our laboratory. Utilizing [(11)C]-TGN-020, PET images were successfully generated in wild type and AQP4 null mice, providing a basis for future evaluation regarding its suitability for clinical studies.