NLX-112, a Selective 5-HT1A Receptor Agonist, Upregulates GDNF and is Neuroprotective Against MPTP-Induced Nigrostriatal Degeneration in a Mouse Model of Parkinson's Disease.

NLX-112 is a potent and selective 5-HT1A agonist that has successfully completed a Phase 2A clinical trial for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease (PD) patients. Here, we investigated the neuroprotective activity of NLX-112 in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Four groups of male mice received subcutaneous administrations of either saline (1 mL/kg) daily for 15 days, MPTP (21.4 mg/kg for 5 days, preceded and followed by 5 days of saline, NLX-112 (1 mg/kg/day for 15 days), or combined MPTP + NLX-112. Two weeks following the cessation of treatments, mice treated with NLX-112 alone or NLX-112/MPTP showed increased locomotor activity and reduced anxiety-like behavior (as assessed by a 40% reduction of thigmotaxis) in an open-field test, consistent with sustained effects of 5-HT1A receptor activation. MPTP-treated mice showed a 40% reduction of dopaminergic (i.e., tyrosine hydroxylase immunoreactive; TH-ir) neurons in the substantia nigra compacta (SNc) and a 55% reduction of nerve terminals in the striatum. NLX-112 treatment completely prevented TH-ir neuron loss and reduced MPTP-induced dopamine nerve terminal loss to 30%. MPTP also markedly increased the levels of GFAP-ir astrocytes and Iba1-ir microglia in the SN, as well as coexpression of glial-derived neurotrophic factor (GDNF) in the GFAP-ir astrocytes in both the SNc and the striatum. NLX-112 markedly reversed this MPTP-induced microglial overactivation in the SNc, and upregulated GFAP/GDNF colocalization in both the striatum and the SNc. Overall, the present study demonstrates a robust neuroprotective effect of NLX-112 in a mouse model of PD by preventing microgliosis, upregulating GDNF, and favoring sustained pro-locomotor activity.