Cannabinoid Type 2 Receptor (CB2R) as a promising therapeutic target to manage inflammatory based diseases, including neurodegeneration and SARS-CoV-2 infection

During my PhD, I had the chance to investigate the therapeutic potential of two emerging CB2 receptor (CB2R) ligands, beta-caryophyllene (BCP) and FD-22a, in managing inflammatory-based diseases, with a specific focus on Alzheimer’s disease (AD) and SARS-CoV-2 infection. CB2R, recognized for its pivotal role in modulating immune and inflammatory responses, emerged as a promising target for addressing the pathological mechanisms underlying these conditions. The first aim of my research was to evaluate the anti-inflammatory and neuroprotective effects of BCP in preclinical models of neurodegeneration. BCP demonstrated a strong ability to reduce β-amyloid (Aβ)-induced toxicity both in human microglial cells (HMC3) and in murine organotypic brain slice cultures (BSCs). Through CB2R and PPAR-γ activation, BCP effectively suppressed pro-inflammatory cytokine release, restored anti-inflammatory markers, and counteracted the detrimental effects of Aβ on brain-derived neurotrophic factor (BDNF), a key regulator of neuronal health and plasticity. These findings were further validated in vivo in an APP/PS1 mouse model of AD. A six-month collaboration at the Hospital del Mar Research Institute in Barcelona enabled us to demonstrate that BCP significantly improved cognitive performance, restored synaptic plasticity, and reversed BDNF deficits in this murine model, highlighting its multifaceted neuroprotective role. The second focus of my research involved the evaluation of the neuroprotective and anti-inflammatory effects of FD-22a, a novel synthetic CB2R bitopic/dualsteric ligand. This compound was investigated for its ability to address β-amyloid-induced cytotoxicity in microglial (HMC3) and glioblastoma (U87-MG) cell lines. FD-22a exhibited a potent protective effect by activating the autophagy–lysosome pathway (ALP) through TFEB-dependent mechanisms. Quantitative proteomic analysis revealed that FD-22a modulated the CLEAR signaling network, restoring cellular clearance mechanisms disrupted by Aβ. By enhancing autophagic flux and reducing inflammation, FD-22a represents a promising candidate for the treatment of neurodegenerative diseases characterized by autophagic impairments and neuroinflammation. Beyond its application in AD, my research also explored the potential of BCP in mitigating the cytokine release syndrome (CRS) associated with SARS-CoV-2 infection. Using a model of LPS-induced inflammation in human alveolar epithelial cells (A549), we demonstrated that BCP was able to significantly reduce pro-inflammatory cytokine release and downregulated ACE2 expression, which is critical for viral entry into the host cell. These findings suggest that BCP not only holds therapeutic potential for COVID-19 but could also be applied to other ACE2-related diseases, such as other viral infections and chronic inflammatory conditions influenced by ACE2 dysregulation. In conclusion, my doctoral research provides compelling evidence for the therapeutic potential of BCP and FD-22a as CB2R ligands for the treatment of neurodegeneration and inflammatory-based diseases. BCP’s dual-action mechanism, targeting both inflammation and neuroprotection, and FD-22a’s ability to restore autophagic deficits, underscore the versatility of CB2R as a therapeutic target. These findings pave the way for future studies aimed at developing new therapeutic strategies, optimizing drug delivery systems, and exploring broader applications of CB2R ligands in both neurodegenerative and inflammatory-based diseases.