Research Paper: The Anti-Parkinsonism Effects of KATP Channel Blockade in the 6-Hydroxydopamine-Induced Animal Model: The Role of Oxidative Stress

Abstract

Introduction:Studies suggest that ATP-sensitive potassium (KATP) channels are a potential pharmacotherapeutic target for neuroprotection in neurodegenerative diseases. The current study aimed at evaluating the effect of pretreatment with glibenclamide (Glib) and B vitamins supplement on the severity of behavioral symptoms in 6-hydroxydopamine (OHDA)-induced Parkinsonism. Also malondialdehyde (MDA) concentration was measured in the blood and brain suspensions to find probable neuroprotective mechanism of Glib.Methods:The 6-OHDA was injected into striatum of rats by stereotaxic surgery. Treatment with Glib and B vitamins was started before the surgery and continued up to 3 weeks after that. Development and severity of Parkinsonism were evaluated by conventional behavioral tests. MDA values were measured spectrophotometrically using thiobarbituric acid and MDA standard curve.Results:Pretreatments with Glib, at both doses of 1 and 5 mg/kg or B vitamins significantly ameliorated severity of the behavioral symptoms. Pretreatment with a combination of Glib and B vitamins was more effective than pretreatment with Glib or B vitamins alone. Also, pretreatment with B vitamins, Glib, or a combination of them reduced MDA concentration in the brain suspensions. Decrease in MDA concentration in the group of rats that received a combination of B vitamins and Glib was more prominent than that of the Glib groups.Conclusion:As severity of the behavioral symptoms in the 6-OHDA-induced Parkinsonism reflects the degree of the lesion in Substantia Nigra (SN) dopaminergic neurons, it is suggested that Glib pretreatment has neuroprotective effect against 6-OHDA-induced neurotoxicity. The current study data also showed that this effect may be mediated by antioxidant effect of Glib.

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

“…Mercuri and co-workers demonstrated that K ATP in SNc DAergic neurons are gated by the mitochondrial toxin rotenone [35] and inhibited by memantine, a non-competitive glutamate NMDA receptor antagonist which showed neuroprotective efficacy in animal models [36]. A more recent study reported the neuroprotective effect of K + ATP blockade in PD animal models [37]. In this work, the K ATP blocker and antidiabetic glibenclamide was able to protect from 6−OHDA-induced nigrostriatal lesion.…”

Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation

“…The therapeutic potential of sulfonylureas in PD has been investigated in preclinical studies. Sulfonylureas improve motor and memory impairment, decrease oxidative stress, attenuate α-synuclein expression, and prevent dopaminergic neuronal damage and apoptosis in toxininduced experimental PD (Abdelkader et al, 2020;Ishola et al, 2019;Piri et al, 2017;Qiu et al, 2021). A reduction of microglia pro-inflammatory response, pro-inflammatory cytokines release, iNOS expression, and NF-κB activation was observed in the brain tissue of rodents induced to PD (Abdelkader et al, 2020;Ishola et al, 2019;Qiu et al, 2021).…”

Altered neural cell junctions and ion-channels leading to disrupted neuron communication in Parkinson’s disease

“…Kir6.2-antisense oligo-DNAs were administered into GP, for the case of 6−OHDA hemiparkinsonian rat, which reduced the expressibility of Kir6.2-mRNA, thereby reducing apomorphine-induced the other side turns in the models. Pre-treatment of rodents with 6−OHDA induced abnormalities in PD with glibenclamide shows improvements in severe behavioral-symptoms 182 . Use of NaHS reduced 6−OHDA related behavioral symptoms and cellular damage of DA cells in the SN 183 .…”