JWH-051

Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling. In SAMP8 mice (sporadic AD model), we evaluated the effects of pharmacological inhibition of G9a (UNC0642), combined with CB₁R agonism (ACEA) and/or CB₂R agonism (JWH133), on cognitive recovery, neuronal morphology, and neuroinflammation. Our results demonstrated that SAMP8 mice treated with UNC0642 and ACEA exhibited significant recovery in short-term memory, as assessed by the Novel Object Recognition Test (NORT), and complete recovery of spatial memory in the Object Location Test (OLT). These improvements were accompanied by enhanced neuronal morphology (increased dendritic length and density) and reduced neuroinflammation markers, suggesting a synergistic effect of G9a inhibition and CB₁R activation. Importantly, JWH133 treatment, both alone and in combination with UNC0642, resulted in a pronounced reduction of neuroinflammatory markers (Trem2, Cd33, iNOS) and a significant restoration of dendritic spine density and branching length, with the dual treatment showing the most robust effects. JWH133 alone produced moderate cognitive improvement, but its combination with G9a inhibition led to outcomes comparable to those of control animals. Thus, the results underscore G9a inhibition's potential to amplify cannabinoid receptor-mediated neuroprotection while mitigating psychoactive risks, offering a promising multi-target approach for neurodegenerative diseases.

Tuberculosis (TB) is one of the leading causes of death worldwide and a major public health problem. Immune evasion mechanisms and antibiotic resistance highlight the need to better understand this disease and explore alternative treatment approaches. Mycobacterial infection modulates the macrophage response and metabolism to persist and proliferate inside the cell. Cannabinoid receptor type 2 (CB2) is expressed mainly in leukocytes and modulates the course of inflammatory diseases. Therefore, our study aimed to evaluate the effects of the CB2-selective agonist GP1a on irradiated Mycobacterium bovis-BCG (iBCG)-induced J774A.1 macrophage activation. We observed increased expression of CB2 in macrophages after iBCG stimulation. The pretreatment with CB2-agonists, GP1a, JWH-133, and GW-833972A (10 µM), reduced iBCG-induced TNF-α and IL-6 release by these cells. Moreover, the CB2-antagonist AM630 (200 nM) treatment confirmed the activity of GP1a on CB2 by scale down its effect on cytokine production. GP1a pretreatment (10 µM) also inhibited the iBCG-induced production of inflammatory mediators as prostaglandin (PG)E2 and nitric oxide by macrophages. Additionally, GP1a pretreatment also reduced the transcription of proinflammatory genes (inos, il1b, and cox2) and genes related to lipid metabolism (dgat1, acat1, plin2, atgl, and cd36). Indeed, lipid droplet accumulation was reduced by GP1a treatment, which was partially blockade by AM630 pretreatment. Finally, GP1a pretreatment reduced the activation of the NF-κB signaling pathway. In conclusion, the activation of CB2 by GP1a modulated the macrophage response to iBCG by reducing inflammatory mediator levels and metabolic reprogramming.