URB597 reduces biochemical, behavioral and morphological alterations in two neurotoxic models in rats

Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ1-42 peptide in rat hippocampal neurons

“…We have chosen AEA, WIN 55,212-2 and URB597 as they were effective protective agents against loss of cell viability and oxidative stress, and we investigated whether their effects were linked to intrinsic antioxidant properties of these compounds. It was expected for URB597 to display the best antioxidant profile, beyond its already proven capacity to inhibit FAAH to accumulate endocannabinoids such as AEA (Howlett and Abood, 2017;Maya-López et al, 2017). This rationale also emerged from previous observations by other groups demonstrating that URB597 reduces the superoxide radical formation in a toxic model of ethanol intake (Pelicao et al, 2016), while decreasing lipid peroxidation in other toxic models (Maya-López et al, 2017;Escamilla-Ramírez et al, 2017).…”

“…It was expected for URB597 to display the best antioxidant profile, beyond its already proven capacity to inhibit FAAH to accumulate endocannabinoids such as AEA (Howlett and Abood, 2017;Maya-López et al, 2017). This rationale also emerged from previous observations by other groups demonstrating that URB597 reduces the superoxide radical formation in a toxic model of ethanol intake (Pelicao et al, 2016), while decreasing lipid peroxidation in other toxic models (Maya-López et al, 2017;Escamilla-Ramírez et al, 2017). Our results revealed that the endocannabinoid AEA and the synthetic cannabinoid WIN 55,212-2 exhibited antioxidant capacity as peroxyl radical scavengers, and this property might account for the protective profiles of these two agents, although the level of contribution of their antioxidant capacity deserves more detailed characterization.…”

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

“…Currently, several classes of reversible and irreversible covalent FAAH inhibitors have been developed, such as URB597, OL-135, PF-3845, AM3506, PF-04457845, JNJ-40355003, JNJ-42165279, JNJ-1661010, and BIA 10-2474, although the majority of studies have involved URB597. The irreversible covalent URB597 promoted the increase in endocannabinoid anandamide by inhibiting FAAH activity [ 145 , 146 ]. Furthermore, URB597 efficiently suppressed glutamate Aβ42-induced toxicity in primary hippocampal neurons and stimulated the mitochondrial membrane potential [ 147 ].…”

(Endo)Cannabinoids and Cognitive Functions in Animals: Healthy and Pathological Brain

“…The majority of studies involved URB597, although several classes of reversible and irreversible covalent FAAH inhibitors have been developed, such as URB597, JNJ-40355003, and JNJ-42165279. URB597 promoted an increase in the endocannabinoid anandamide by inhibiting FAAH activity [126,127]. Furthermore, URB597 efficiently suppressed Aβ42-induced glutamate toxicity in primary hippocampal neurons and stimulated the mitochondrial membrane potential [128].…”