Liraglutide Improves Cognitive and Neuronal Function in 3-NP Rat Model of Huntington’s Disease

Abstract

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington’s disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide 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 it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the p-GSK-3β/p-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/p-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

“…Neuroinflammation is involved in a number of neurodegenerative illnesses, including PD, AD, and HD, where activation of astrocytes and microglia is evident. 62 Herein, our results revealed that repaglinide mitigated the robust microgliosis and astrocytic activation and subsequent neuronal inflammation as reflected in the substantial reduction in Iba1 and GFAP immunostaining as well as IL-6 and IL-1β levels, suggesting its anti-inflammatory properties. The excessively activated microglia and astrocytes coexisted with rotenone exposure were previously echoed in a PD rat model, along with its exacerbating effect on neuronal apoptosis and neuroinflammation.…”

Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK-3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high-fat diet- streptozocin rat model

“…This was in agreement with the study of Wang et al, who postulated that old diabetic rats displayed reduced spatial learning and short- and long-term memory [ 52 ]. Treatment with either liraglutide [ 47 ] or pramlintide [ 9 ] resulted in more or less normal results of spontaneous T maze as well as NOR test in both treated groups as compared to the diabetic group.…”

“…Other studies discussed how PRAM might improve cognitive function considering the importance of the native role of amylin in the regulation of oxidative processes and neuronal function [ 39 ]. Anti-apoptotic properties and oxidative stress reduction of PRAM and LIRA therapy seem to contribute to neurological recovery [ 11 , 28 , 47 , 62 ]. A similar finding was observed by Patrick et al, who stated that amylin treatment revealed restored lost mitochondrial membrane potential [ 39 ].…”

Neuroprotective potential of the Amazonian fruits Euterpe oleracea Mart. and Paullinia cupana Kunth

“…AD affects approximately 55 million people worldwide and is more frequent between 75 and 84 years old (Alzheimer's Association, 2021; WHO, 2022), whereas PD is the second most prevalent neurodegenerative disease affecting 2-3% of the population over 65 years old (Poewe et al, 2017). Moreover, HD, which affects 5 to 7 individuals per 100,000 inhabitants aged between 30 and 50 years (Bruzelius et al, 2019), is also an important neuropathology (Shawki et al, 2021). In a simplified way, AD, PD, and HD mainly impair neuronal structures and functions in part due to the aberrant accumulation of certain aggregated proteins: amyloid-beta (Aβ) in AD, α-synuclein in PD (Kulenkampff et al, 2021;Shawki et al, 2021), and huntingtin (HTT) in…”

“…Moreover, HD, which affects 5 to 7 individuals per 100,000 inhabitants aged between 30 and 50 years (Bruzelius et al, 2019), is also an important neuropathology (Shawki et al, 2021). In a simplified way, AD, PD, and HD mainly impair neuronal structures and functions in part due to the aberrant accumulation of certain aggregated proteins: amyloid-beta (Aβ) in AD, α-synuclein in PD (Kulenkampff et al, 2021;Shawki et al, 2021), and huntingtin (HTT) in…”