A study of the possible curative effect of Liraglutide {u2013} a Glucagon-like Peptide -1 analog - on cognitive deficits in 3-Nitropropionic acid {u2013}Induced Huntington{u2019}s Disease in rats / Samar Mamdouh Mohamed Shawki ; Supervised Hanan S. Eabhar , Walaa Wadie Ibrahim , Rania Mohammed Rahmo

Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Introduction: Huntington{u2019}s disease (HD) is a dominant autosomal neurodegenerative disease associated with progressive motor and cognitive deficits that lacks a definitive symptomatic therapy. The antidiabetic liraglutide possesses a neuroprotective potential against models of neurodegenerative disorders; however, its role in HD remains elusive which is the aim of this work. Methods: Liraglutide (200 og/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Results: Liraglutide abated the 3-NP-induced neurobehavioral deficits tested by open field and elevated plus maze tests, effects that were mirrored on the improved histopathological findings. To further emphasize its neuroprotective role, liraglutide markedly downregulated the striatal mRNA expression of HSP 27, PBR and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. Additionally, it enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt and p-CREB, besides modulating the p-GSK-3Ý/p-Ý-catenin axis. Liraglutide also proved its anti-oxidant/-apoptotic capacity that were verified by enhancing the antioxidant transcription factor Nrf2 and abrogating MDA, besides, upregulating both Bcl2 and Bcl-XL and downregulating Bax along with decreasing caspase-3 activity. Conclusion: based on these findings, liraglutide exerts a neuroprotective effect on 3-NP treated rats that is at least partially attributed to the increase of miR-130a and modulation of PI3K/Akt/CREB/BDNF/TrKB, sortilin and p75NTR, and Akt/ GSK-3Ý/p-Ý-catenin trajectories besides its anti-apoptotic, antioxidant, and neurotrophic activities

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