The Synthetic Cannabinoid AKB-48 Induces Cell Death in Murine Cerebellum Through Different Signaling Pathways

Novel psychoactive substances (NPSs) exhibit extremely strong pharmaco-toxicological activity, often leading to severe adverse effects that pose a serious risk to consumers' health. Among these, synthetic cannabinoids (SCs) currently represent the majority of drug seizures in Europe. One such compound, AKB-48 (also known as APINACA), was first identified in Japanese herbal smoking blends in 2012. Although it mimics the effects of Δ9-THC, the primary psychoactive component of Cannabis sativa, AKB-48 can induce more severe and potentially life-threatening outcomes. Several in vivo studies investigating the acute administration of AKB-48 have reported profound behavioral, neurological, and neurochemical alterations, including disruptions of neurotransmission across multiple brain regions, thus confirming its neurotoxic potential. Given the recognized vulnerability of the cerebellum to NPS, and its critical role in integrating neural circuits affected by psychostimulant drugs, the present study evaluated the toxic effects of repeated AKB-48 exposure on the cerebellar cortex of adult male and female ICR-CD1^® mice. Particular attention was paid to the modulation of cell death pathways, alongside assessments of sensorimotor responses. The results demonstrate, for the first time, that repeated AKB-48 administration induces significant morphological, immunohistochemical, and ultrastructural changes in both male and female mice. These alterations included pronounced disruption of cerebellar architecture and marked modulation of cell death pathways, further corroborated by TEM-detected ultrastructural damage and a substantial reduction in the basal visual placing response. Overall, the findings provide clear evidence of AKB-48's sex-independent neurotoxicity, leading to cerebellar alterations that ultimately result in neuroplasticity impairment.