Neurotrophic Factors Attenuate Glutamate‐Induced Accumulation of Peroxides, Elevation of Intracellular Ca²⁺ Concentration, and Neurotoxicity and Increase Antioxidant Enzyme Activities in Hippocampal Neurons

Abstract

Exposure of cultured rat hippocampal neurons to glutamate resulted in accumulation of cellular peroxides (measured using the dye 2,7‐dichlorofluorescein). Peroxide accumulation was prevented by an N‐methyl‐d‐aspartate (NMDA) receptor antagonist and by removal of extracellular Ca2+, indicating the involvement of NMDA receptor‐induced Ca2+ influx in peroxide accumulation. Glutamate‐induced reactive oxygen species contributed to loss of Ca2+ homeostasis and excitotoxic injury because antioxidants (vitamin E, propyl gallate, and N‐tert‐butyl‐α‐phenylnitrone) suppressed glutamate‐induced elevation of intracellular Ca2+ concentration ([Ca2+]i) and cell death. Basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and brain‐derived neurotrophic factor (BDNF), but not ciliary neurotrophic factor, each suppressed accumulation of peroxides induced by glutamate and protected neurons against excitotoxicity. bFGF, NGF, and BDNF each increased (to varying degrees) activity levels of superoxide dismutases and glutathione reductase. NGF increased catalase activity, and BDNF increased glutathione peroxidase activity. The ability of the neurotrophic factors to suppress glutamate toxicity and glutamate‐induced peroxide accumulation was attenuated by the tyrosine kinase inhibitor genistein, indicating the requirement for tyrosine phosphorylation in the neuroprotective signal transduction mechanism. The data suggest that glutamate toxicity involves peroxide production, which contributes to loss of Ca2+ homeostasis, and that induction of antioxidant defense systems is a mechanism underlying the [Ca2+]i‐stabilizing and excitoprotective actions of neurotrophic factors.

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…Akt is also known to induce the expression of survival genes such as Bcl-2 and Bcl-xl, by activating CREB and nuclear factor-kB (Downward, 2004). Though the ability of rhEPO to maintain BDNF levels may limit several adverse cellular effects of HAL, including a reduction in brain glutathione levels, decreased antioxidant enzyme expression, enhanced oxidative stress (Behl et al, 1995;Pillai et al, 2007b;Sagara, 1998;Shivakumar and Ravindranath, 1992;Yokoyama et al, 1998), and changes in cholinergic neuronal markers (Mahadik et al, 1988;Terry et al, 2003) since BDNF has already been found to prevent changes in these molecules (Mattson et al, 1995).…”

Neurovascular Protection by Targeting Early Blood–Brain Barrier Disruption with Neurotrophic Factors after Ischemia–Reperfusion in Rats

“…T 2 relaxometry was performed using a spin echo (SE) sequence with a repetition time (TR) of 4,000 ms and data sets were acquired at 7 echo times (TE): 29, 58, 88, 117, 146, 175, and 204 ms. Treated groups were subjected to serial MR imaging at pre-designated time points (24,48, 96 hours and 1 week) after reperfusion. T 2 -weighted turbo spin echo (T 2 -TSE) sequences were used to visualize the temporal and spatial changes in vasogenic edema formation (T 2 lesion).…”

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor

“…In addition, BDNF holds a well-established role in protecting neurons against insults. For example, BDNF gene deletion in mice increases the incidence of apoptosis (Linnarsson et al, 1997) and addition of BDNF in cultured rat hippocampal neurons suppresses accumulation of peroxides and protects neurons against excitotoxicity (Mattson et al, 1995). BDNF may partake in a protective mechanism that exercise employs to protect the brain from insults or risk factors imposed by a HF diet, possibly by influencing downstream effectors such as CREB and synapsin I.…”