Objective: To investigate whether NLX-112, a potent and selective 5-HT_1A agonist is neuroprotective in a mouse MPTP model of Parkinson’s Disease (PD) [1].

Background: There is evidence for neuroprotective effects of 5-HT_1A  agonists. NLX-112 is a potent and selective 5-HT_1A agonist [2] currently undergoing clinical development for L-DOPA-induced dyskinesia in PD.

Method: Four groups of mice received either saline (1ml/kg), MPTP (5×25 mg/kg / 5 days), NLX-112 (1mg/kg 15 days) or MPTP+NLX-112 (s.c). Immunoreactivity (-ir) for tyrosine-hydroxylase (TH, expressed in DA neurons), glial fibrillary associated protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1) and glial derived neurotrophic factor (GDNF) was investigated in the substantia-nigra (SN) and striatum. The extent of MPTP-induced TH+ve cell loss in the SN and the loss of striatal fibres was assessed in the presence and absence on NLX-112. The extent of microgliosis, astrocytosis and co-localisation with GDNF was also assessed in all 4 groups of animals.

Results: Compared to saline treated mice, MPTP caused a significant loss of TH+ve neurons in the SN (approx. 30%) and TH+ve fibre density in the striatum (approx. 60%). Pre-treatment with 1mg/kg NLX-112 significantly reversed MPTP-induced cell loss resulting in cell numbers in the SN that was not significantly different to control. Similarly, in the striatum, TH-r nerve terminal loss was signficantly reversed by 50%. MPTP significantly increased the number of GFAP-ir, an effect which was significantly reversed by NLX-112. In the MPTP-treated animals striatal GFAP-GDNF colocalisation was significantly increased by 110% which was increased even further by 330% in the presence of NLX-112. In the SN, GFAP-GDNF co-localisation was unchanged by MPTP compared to control, but was NLX-112 treatment significantly increased co-localisation by 173%. Furthermore, MPTP significantly increased Iba1-ir by 117% in the SN, an effect almost abolished by NLX-112.

Conclusion: NLX-112 exhibits neuroprotective properties in MPTP treated mice by reversing the loss of nigral striatal TH-ir. NLX-112’s neuroprotective effects are likely mediated through reversal of MPTP induced inflammation as shown by attenuation of astrogliosis, inhibition of microgliosis but also upregulation of the neurotrophic factor, GDNF [3] in astrocytes.

References: [1] Przedborski, S., Jackson‐Lewis, V., Naini, A.B., Jakowec, M., Petzinger, G., Miller, R. and Akram, M., 2001. The parkinsonian toxin 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP): a technical review of its utility and safety. Journal of neurochemistry, 76(5), pp.1265-1274.

[2] Newman-Tancredi, A., Martel, J.C., Cosi, C., Heusler, P., Lestienne, F., Varney, M.A. and Cussac, D., 2017. Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist. Journal of Pharmacy and Pharmacology, 69(9), pp.1178-1190.

[3] Behl, T., Kaur, I., Kumar, A., Mehta, V., Zengin, G. and Arora, S., 2020. Gene therapy in the management of Parkinson’s disease: potential of gdnf as a promising therapeutic strategy. Current Gene Therapy, 20(3), pp.207-222.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-neuroprotective-properties-of-nlx-112-in-mptp-treated-mice-are-mediated-by-reactive-gliosis-and-astrocytic-gdnf/