Abstract
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.
Highlights
** p < 0.01 vs control group and # p < 0.05, ## p < 0.01 vs glutamate-injected group. n.s = non-significant difference. These results demonstrate that glutamate administration disrupts cellular redox homeostasis, leading to increased brain oxidative stress, while the estradiol treatment could protect against the glutamate-induced neurotoxicity by improving the endogenous antioxidant activity through regulating cytoprotective enzymes (GSH and heme oxygenase 1 (HO-1)) in postnatal rat brain
We focused on the excitotoxicity of glutamate-induced reactive oxygen species (ROS) production that leads to dysregulation of MAP kinase-mediated neuroinflammation, synaptic dysfunction, and neurodegeneration in the cortical and hippocampal brain region of postnatal day 7 (P7) rats
These data demonstrate that glutamate-induced oxidative stress (ROS)
Summary
Glutamate is a free amino acid, rich in CNS and known as a major excitatory neurotransmitter, connected to essentially most activities of the nervous system [1], including fast synaptic communication, neuronal plasticity, survival and outgrowth [2]. Under pathological conditions, glutamate plays a crucial role in neuronal cell death [3], and its dysregulation has been reported in both acute and chronic neurodegenerative disease, including ischemia, amyotrophic lateral sclerosis, Huntington’s disease and Alzheimer’s disease (AD) [1,4]. Antioxidants 2021, 10, 892 and damages mitochondrial membrane, inducing neuronal apoptosis and cell death [5,6]. The neuroprotection against glutamate-induced excitotoxicity may present a promising therapeutic strategy in alleviating acute/chronic neurodegenerative disease, at least to delay their onset/appearance [7]
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