Oxidative Stress Affects Synaptosomal γ-Aminobutyric Acid and Glutamate Transport in Diabetic Rats

Abstract

Evidence suggests that oxidative stress is involved in the pathophysiology of diabetic complications and that insulin has a neuroprotective role in oxidative stress conditions. In this study, we evaluated the in vitro effect of insulin in the susceptibility to oxidative stress and in the transport of the amino acid neurotransmitters ␥-aminobutyric acid (GABA) and glutamate in a synaptosomal fraction isolated from male type 2 diabetic Goto-Kakizaki (GK) rat brain cortex. The ascorbate/ Fe 2؉ -induced increase in thiobarbituric acid reactive substances (TBARSs) was similar in Wistar and GK rats and was not reverted by insulin (1 mol/l), suggesting that other mechanisms, rather than a direct effect in membrane lipid peroxidation, may mediate insulin neuroprotection. Diabetes did not affect GABA and glutamate transport, despite the significant decrease in membrane potential and ATP/ADP ratio, and insulin increased the uptake of both GABA and glutamate in GK rats. Upon oxidation, there was a decrease in the uptake of both neurotransmitters and an increase in extrasynaptosomal glutamate levels and in ATP/ADP ratio in GK rats. Insulin treatment reverted the ascorbate/Fe 2؉ -induced decrease in GABA accumulation, with a decrease in extrasynaptosomal GABA. These results suggest that insulin modulates synaptosomal GABA and/or glutamate transport, thus having a neuroprotective role under oxidizing and/or diabetic conditions.

Insulin in the Brain: Sources, Localization and Functions

“…Duarte et al have evaluated the effects of insulin on the cerebral synaptosomes in control and oxidative stress conditions and shown that, under oxidative stress, GABA and glutamate uptake is decreased and these neurotransmitters accumulate in the extrasynaptosomal space, while the addition of insulin reverses these changes. Duarte et al [280,281] reported that the oxidative stress-induced increment of thiobarbituric acid-reactive substances (TBARSs) could not be reversed by insulin, and since TBARSs is well known as an indicator of lipid peroxidation, modifying membrane lipid peroxidation is not involved in the insulin neuroprotection against oxidative stress. These authors have concluded that the neuromodulatory effects of insulin should be the main mechanism underlying insulin neuroprotection [280,281].…”

Effects of Cyclohexanonic Long-Chain Fatty Alcohol, tCFA15 on Amino Acids in Diabetic Rat Brain: A Preliminary Study

“…Recent studies showed that L-arginine ameliorates oxidative stress in alloxaninduced experimental diabetes mellitus [52], and that oxidative stress affects GABA and glutamate transport in diabetic rats [39]. Arginine might play a role in oxidative stress in the brain of diabetes.…”

“…However, the excess release of glutamate is known to induce insults such as neurotoxicity or cell death. Previous studies reported that glutamate uptake rates were decreased in the cortex slices of STZ-induced diabetes [38] and in the Data are shown as mean ± SEM (lM/g tissue weight) of six to eight separated determinations in each group * P \ 0.05 compared with normal controls ** P \ 0.01 compared with normal controls *** P \ 0.001 compared with normal controls # P \ 0.05 compared with diabetes cortex synaptosomes of spontaneous diabetes [39], supporting the present study. In clinical studies, depressed patients had an increase in plasma levels of glutamate [40][41][42].…”

Encefalopatia Diabética E Depressão: Dano Oxidativo No Cérebro

“…Anteriormente, Rajtar et al 69 verificaram que o clonazepam exerce um efeito inibitório in vitro sobre a produção de ERO, sugerindo que o clonazepam possa causar uma diminuição da ativação plaquetária e da liberação de mediadores pró-inflamatórios por neutrófilos ativados. A insulina tem efeito na função cognitiva 70 , devido à sua ação neuroprotetora em condições diabéticas e oxidativas 71 . A produção excessiva de radicais livres de oxigênio que pode ocorrer em pacientes com diabetes induz a uma variedade de lesões em macromoléculas, incluindo o DNA.…”

“…A insulina e os hipoglicemiantes, que são tradicionalmente utilizados no tratamento do diabetes e suas complicações, apresentam entre seus efeitos uma ação antioxidante, como já mostrado em diversos estudos 23,71,72,77 . Sendo assim, as pesquisas atuais com modelo experimental de diabetes têm buscado novos antioxidantes como uma abordagem terapêutica para o tratamento ou prevenção da encefalopatia diabética.…”