(833.7) LRRK-2 Inhibition By PF06447475 Treatment Reduces Neuronal Damage and Immune Response After Spinal Cord Trauma

Poster Board Number: B22

Alessia Filippone (University of Messina), Giovanna Casili (University of Messina), Marika Lanza (University of Messina), Deborah Mannino (University of Messina), Rossella Basilotta (University of Messina), Michela Campolo (University of Messina), Irene Paterniti (University of Messina), Salvatore Cuzzocrea (University of Messina), Emanuela Esposito (University of Messina)

Spinal Cord Injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade and immune system. Dysregulated or non-resolving inflammatory processes can affect neuronal homeostasis and drive immune cells stimulation. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with the progression of Parkinson’s disease (PD), and its kinase activity was found to be upregulated after instigated inflammation of the Central Nervous System (CNS) and immune system activation. Here, we aimed to investigate the efficacy of PF-06447475, an LRRK2 inhibitor, by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord at T6-T8 levels, then mice were treated with PF-06447475 (2.5-5 and 10 mg/kg o.s) 1 and 6 hrs after SCI. We found that PF-06447475 treatments at the higher doses (5 and 10 mg/kg) showed great abilities to reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. In addition, cytokines expression levels including interleukins (IL-1, IL-6, IL-10 and12),interferong(IFN-g)and tumor necrosis factor-α (TNF-α secreted and released by immune cells after trauma were decreased by LRRK-2 inhibitor treatments. Moreover, the accumulation of CD4+and CD8+cells throughout the spinal cord lesion site of SCI mice was reduced by PF-06447475 oral administration at the dose of 10 mg/kg. Taken together, our results suggest that exist a mutual correlation between LRRK2, neurodegeneration and immunity and that LRRK2 inhibition could have direct effects on the intervention of neuroinflammatory disorders.