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Dysregulated glutamate signaling, leading to neuronal excitotoxicity and death, has been associated with neurodegenerative pathologies. 17β-estradiol (E2) is a human steroid hormone having a role in reproduction, sexual maturation, brain health and biological activities. The study aimed to explain the neuroprotective role of E2 against glutamate-induced ROS production, MAP kinase-dependent neuroinflammation, synaptic dysfunction and neurodegeneration in the cortex and hippocampus of postnatal day 7 rat brain. Biochemical and immunofluorescence analyses were applied. Our results showed that a single subcutaneous injection of glutamate (10 mg/kg) induced brain oxidative stress after 4 h by disturbing the homeostasis of glutathione (GSH) and revealed an upsurge in ROS and LPO levels and downregulated the expression of Nrf2 and HO-1 antioxidant protein. The glutamate-exposed P7 pups illustrated increased phosphorylation of stress-activated c-Jun N-terminal kinase (JNK) and p38 kinase (p38) and downregulated expression of P-Erk1/2. This was accompanied by pathological neuroinflammation as revealed by enhanced gliosis with upregulated expression of GFAP and Iba-1, and the activation of proinflammatory cytokines (TNF-α) in glutamate-injected P7 pups. Moreover, exogenous glutamate also reduced the expression of synaptic markers (PSD-95, SYP) and induced apoptotic neurodegeneration in the cortical and hippocampal regions by dysregulating the expression of Bax, Bcl-2 and caspase-3 in the developing rat brain. On the contrary, co-treatment of E2 (10 mg/kg) with glutamate significantly abrogated brain neuroinflammation, neurodegeneration and synapse loss by alleviating brain oxidative stress by upregulating the Nrf2/HO-1 antioxidant pathway and by deactivating pro-apoptotic P-JNK/P-p38 and activation of pro-survival P-Erk1/2 MAP kinase pathways. In brief, the data demonstrate the neuroprotective role of E2 against glutamate excitotoxicity-induced neurodegeneration. The study also encourages future studies investigating if E2 may be a potent neuroprotective and neurotherapeutic agent in different neurodegenerative diseases.

Advances in medicine and dietary standards over recent decades have remarkably increased human life expectancy. Unfortunately, the chance of developing age-related diseases, including neurodegenerative diseases (NDDs), increases with increased life expectancy. High metabolic demands of neurons are met by mitochondria, damage of which is thought to contribute to the development of many NDDs including Parkinson's disease (PD). Mitochondrial damage is closely associated with the abnormal production of reactive oxygen species (ROS), which are widely known to be toxic in various cellular environments, including NDD contexts. Thus, ways to prevent or slow mitochondrial dysfunction are needed for the treatment of these NDDs. In this review, we first detail how ROS are associated with mitochondrial dysfunction and review the cellular mechanisms, such as the mitochondrial quality control (MQC) system, by which neurons defend against both abnormal production of ROS and the subsequent accumulation of damaged mitochondria. We next highlight previous studies that link mitochondrial dysfunction with PD and how dietary antioxidants might provide reinforcement of the MQC system. Finally, we discuss how aging plays a role in mitochondrial dysfunction and PD before considering how healthy aging through proper diet and exercise may be salutary.