The Neuroprotective and Behavioural Properties of NLX-112 in Models of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder world-wide. The loss of dopamine (DA) producing neurons in the substantia-nigra is considered to be the primary cause of disease pathogenesis with the concomitant loss of neural DA leading to a vast array of debilitating -motor and non-motor symptoms. Therefore, preventing DAergic neuronal degeneration is key to halting the advancement of PD. There is evidence for serotonin 5-HT1A agonists having neuroprotective effects on DA neurons but so far, the most promising results have never extended beyond pre-clinical investigation. NLX-112 is a potent and selective 5-HT1A biased agonist that has had recent success in a phase 2a (Ph2a) clinical trial as a novel therapy for alleviating parkinsonism and levodopa induced dyskinesia. Here, the first evidence is shown indicating that NLX-112 acts as a neuroprotective agent in a neuroblastoma cell line and in C57b/6 mouse (C57b/6J and C57b/Ola-HSD strains). In vitro, modest but significant protection (+10%) of SH-SY5Y cells was achieved with low concentrations of NLX-112 (100μM approx.) against MPP+ and MG132 toxic challenge. In an MPTP mouse model, NLX-112 almost completely reversed the effects of an MPTP-induced 40% SN DA lesion. Further still, this was likely achieved through NLX-112’s tempering of reactive gliosis in the SNpr and striatum, with NLX-112 significantly attenuating microgliosis and astrocytosis. The standout finding from this thesis is the effect that NLX-112 has on enhancing endogenous glial derived neurotrophic factor (GDNF) secretion from astrocytes, which was associated with its neuroprotective property. This is a very important finding, as GDNF is recognised as one of the more promising avenues for neuroprotective treatments in PD. Taken together, the behavioural, biochemical and immunohistochemical data presented in this thesis provides evidence that NLX-112 is neuroprotective against DAergic neurodegeneration in the cellular and mouse models of PD.