Erythropoietin and Bacillus Calmette–Guérin Vaccination Mitigate 3-Nitropropionic Acid-Induced Huntington-like Disease in Rats by Modulating the PI3K/Akt/mTOR/P70S6K Pathway and Enhancing the Autophagy

Abstract

Oxidative stress and mitochondrial dysfunction are among the mechanisms expected to explain the pathogenesis of Huntington's disease. Erythropoietin (EPO) and the Bacillus Calmette−Gueŕin (BCG) vaccine have neuroprotective effects against neurodegenerative diseases; however, the full mechanisms of their action are currently unclear. Here, for the first time, we investigated the neuroprotective effect of BCG vaccination in Huntington-like disease induced by 3-nitropropionic acid (3-NP) and its combination with EPO. Male Wistar rats were randomized into five groups: saline-treated control; 3-NP group (20 mg/kg/day, i.p.) for 7 days; EPO-treated group (5000 IU/kg/day, i.p.) for 14 days after 3-NP administration; live BCG vaccine prophylactic group (5000 cfu/g, i.p.) 10 days prior to 3-NP administration; and live BCG vaccine (5000 cfu/g, i.p.) 10 days before 3-NP administration, followed by EPO treatment (5000 IU/kg/day, i.p.) for 14 days. In a histopathological examination, striatum neurodegeneration was evidenced in the 3-NP injected rats. Administration of 3-NP elevated the levels of p-PI3K, p-Akt, p-mTOR, p-P70S6K, BAX, malondialdehyde, nitric oxide, and cytochrome oxidase while reduced the levels of BCL-2, superoxide dismutase, reduced glutathione, and the autophagy marker microtubule-associated protein light chain 3 in the striatum. EPO and BCG ameliorated the biochemical, histopathological, and behavioral derangements induced by 3-NP, with prominent neuroprotection observed in rats administered the BCG prophylactic combined with EPO treatment. These results highlight the role played by EPO and BCG in the management of 3-NP-induced Huntington-like disease by inhibiting the PI3K/Akt/mTOR/P70S6K pathway and enhancing the autophagy.

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

“…Oxidative stress and mitochondrial dysfunction have an impeccable role in the pathogenesis of neurodegenerative diseases, including PD, , orchestrating the production of ROS that advances the ER stress magnitude . As displayed by our results, the intoxicated rats demonstrated impairment of mitophagy verified by the downregulated PINK1 expression concomitant with a marked decrease in the activity of the antioxidant catalase.…”

“…Recently, our group and others have uncovered multiple therapeutic targets for the treatment of neurodegenerative diseases. ,,, Notably, a rising number of studies suggest that focusing on ER stress in treating neurodegeneration is a feasible therapeutic approach to PD. ,, An earlier work done on IRE1α knockout PD mice model highlighted the chief role of mesencephalic astrocyte-derived neurotrophic factor in mitigating ER stress. By directly binding to IRE1α, it augments UPR and as a result preserves the count of viable dopamine neurons .…”

Erythropoietin Activates Autophagy to Regulate Apoptosis and Angiogenesis of Periodontal Ligament Stem Cells via the Akt/ERK1/2/BAD Signaling Pathway under Inflammatory Microenvironment

“…As the same, the secretions of VEGF-a, FGF-2, and IGF-1 were declined with the increasing concentration of TNF-α, which denoted the decreasing angiogenic level. Taken together, autophagy impaired by TNF-α was considered as a protective factor researches argued that EPO attenuated inflammation, contributed to antiapoptosis, enhanced autophagy, and promoted angiogenesis [13,18,[57][58][59]. Meanwhile, some researches [60][61][62] supported that EPO receptor (EPOR) was expressed in many CD105 + /CD90 + /CD44 + stem cells-such as PDLSCs, dental pulp stem cells, and bone marrow progenitor cells-which demonstrated that the EPO/EPOR signaling pathway played a crucial role in regulating biological behaviors of these cells.…”

“…EPO has been learned as a multifunctional cytokine/drug for wound healing and bone regeneration, particularly in the realm of periodontology [ 54 – 56 ]. An avalanche of researches argued that EPO attenuated inflammation, contributed to antiapoptosis, enhanced autophagy, and promoted angiogenesis [ 13 , 18 , 57 – 59 ]. Meanwhile, some researches [ 60 – 62 ] supported that EPO receptor (EPOR) was expressed in many CD105 + /CD90 + /CD44 + stem cells—such as PDLSCs, dental pulp stem cells, and bone marrow progenitor cells—which demonstrated that the EPO/EPOR signaling pathway played a crucial role in regulating biological behaviors of these cells.…”

“…The Akt signaling pathway always participated in the regulation of apoptosis, autophagy, and angiogenesis [ 27 , 29 ]. Akt was also the main target of EPO, bridging the downstream signal and interacting with autophagy and then stirring up biological activities and determining cell fate [ 58 , 59 , 64 ]. According to RNA-sequencing results, KEGG enrichment demonstrated that the P13K/Akt signaling pathway was significantly upregulated in EPO treatment groups.…”