Neuroprotective Potential of Alkaloid Fractions from Picralima nitida Seeds Against Parkinson’s Disease Pathology: In Vitro and In Vivo Mechanistic Studies

Parkinson's disease (PD) is an increasingly recognised neurodegenerative condition across Nigerian urban populations, where limited access to dopaminergic therapy and the high cost of levodopa-based medicines create an urgent need for affordable, locally derived neuroprotective agents. Picralima nitida, an understory rainforest tree distributed across the South South and South West zones of Nigeria, is used by traditional healers for neurological and pain conditions. Its seeds contain a diverse array of indole alkaloids, including akuammine and pericine, with documented CNS activity. This PhD research systematically evaluates the neuroprotective potential of alkaloid fractions from Picralima nitida seeds against PD pathology through integrated in vitro mechanistic studies and in vivo MPTP-induced PD mouse model evaluation. Alkaloid fractions were isolated by pH-gradient acid-base extraction and column chromatography, and characterised by HPLC, NMR, and HRMS. In vitro neuroprotective mechanisms were investigated in 6-OHDA-challenged SH-SY5Y human neuroblastoma cells, assessing cell viability, mitochondrial membrane potential, ROS generation, caspase-3 activation, and alpha-synuclein aggregation by ThT fluorescence. In vivo evaluation used the MPTP mouse model with rotarod, pole test, and gait analysis for motor function assessment. Tyrosine hydroxylase-positive dopaminergic neuron survival in the substantia nigra was quantified by immunohistochemistry. The akuammine-enriched fraction demonstrated potent neuroprotection in vitro with IC50 of 8.4 ug/mL against 6-OHDA toxicity, reduction of alpha-synuclein aggregation, and mitochondrial protection. In vivo MPTP-treated mice showed significantly improved motor scores and dopaminergic neuron preservation. These results position Picralima nitida alkaloids as priority neuroprotective candidates warranting further development. Keywords: Picralima nitida, neuroprotective, Parkinson's disease, akuammine, alpha-synuclein