Hypoxia‐inducible factor 1 alpha and nuclear‐related receptor 1 as targets for neuroprotection by albendazole in a rat rotenone model of Parkinson's disease

Abstract

Abbreviations: ABZ, albendazole; CoREST, corepressor for repressor element 1 silencing transcription factor; DA, dopamine; GDNF, glial cell line-derived neurotrophic factor; HIF-1α, hypoxia-inducible factor-1 alpha; NF-кB, nuclear factor kappa beta; Nurr1, nuclear receptor related 1; PD, Parkinson's disease; SN, substantia nigra; TH, tyrosine hydroxylase; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor; VMAT, vesicular monoamine transporter. AbstractHypoxia-inducible factor-1 alpha (HIF-1α) and nuclear receptor related-1 (Nurr1) play pivotal roles in the development and survival of dopaminergic neurons, and deficiencies in these genes may be involved in Parkinson's disease (PD) pathogenesis.Recently, anthelminthic benzimidazoles were shown to promote HIF-1α transcription in vitro and were proposed to activate Nurr1 via their benzimidazole group.Therefore, the aim of this study was to explore the neuroprotective effects of albendazole (ABZ), an anthelminthic benzimidazole, in a rotenone model of Parkinson's disease (PD). Rotenone (1.5 mg/kg) was subcutaneously injected into rats every other day for a period of 21 days, resulting in the development of the essential features of PD. In addition to rotenone, ABZ (10 mg/kg) was administered orally starting from the 11th day. Treatment of rats with ABZ markedly mitigated rotenone-induced histological alterations in substantia nigra (SN), restored striatal dopamine (DA) level and motor functions and decreased the expression of α-synuclein (a disease marker protein). ABZ also enhanced expression of Hypoxia-inducible factor-1 alpha (HIF-1α) in the SN along with its downstream target, vascular endothelial growth factor, promoting neuronal survival. Similarly, ABZ augmented nuclear receptor related-1 (Nurr1) expression in the SN and increased transcriptional activation of Nurr1-controlled genes, which are essential for regulation of DA synthesis; additionally, expression of neurotoxic proinflammatory cytokines that induce neuronal death was suppressed.In conclusion, the present study suggests that ABZ exerts a neuroprotective effect in a rotenone-induced PD model associated with HIF-1α and Nurr1 activation and thus may be a viable candidate for treating PD.

Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite—Urolithin A—In the Brain

“…Moreover, along with the neuronal loss in the SN [61,62] and motor impairment [61], the accumulation of α-synuclein, a hallmark of PD, in rats exposed to chronic subcutaneous low doses of rotenone has been recently reported [61,62]. α-Synuclein accumulation is thought to underlie the neurodegeneration in PD.…”

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

“…Second, the neuroprotective impact of repaglinide was studied on male Wistar rats, preferably it should be evaluated in different gender and species due to the difference in the metabolic rates. Third, the employed rotenone model is the low aggressive dose which is a well-reproducible model validated in multiple studies. ,, Fourth, we did not use a positive control group using approved drugs; however, future studies could evaluate the effect of repaglinide on levodopa-induced dyskinesia. Nevertheless, this study is the initiative to prove the neuroprotective action of the antidiabetic drug repaglinide on striatal ER stress, which needs to be extended on the remaining UPR arms.…”

Impact of the apelin/APJ axis in the pathogenesis of Parkinson’s disease with therapeutic potential

“…Furthermore, hypoxia could promote apelin expression in human adipocytes via the hypoxia‐inducible factor 1α (HIF‐1α) (Geiger et al., 2011). HIF‐1α plays a crucial role in the survival of dopaminergic neurons, and upregulation of its expression has been demonstrated to play a neuroprotective role in animal models of PD (Kandil et al., 2019). Additionally, some bone morphogenic proteins (BMPs)—which belong to the transforming growth factor‐β (TGF‐β) family—such as BMP4 and 7 could reduce apelin expression in endothelial cells (Poirier et al., 2012).…”