Activation of the Melanocortin-4 Receptor Prevents Oxidative Damage and Mitochondrial Dysfunction in Cultured Hippocampal Neurons Exposed to Ethanol

Quintanilla, Rodrigo A.; Pérez, Marı́a José; Aránguiz, Alejandra; Tapia-Monsalves, Carola; Mendez, Gloria

doi:10.1007/s12640-020-00204-1

Cited by 14 publications

(8 citation statements)

References 68 publications

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“…11 Furthermore, MC4R activation has been associated with neuron protection in the hippocampus after an ischemic attack by decreasing inflammatory and apoptotic responses, promoting antioxidant defense, and reducing mitochondrial damage. 40,41 Excessive production of free radicals causes oxidative damage that leads to chronic diseases such as cancer, ischemia, atherosclerosis, Alzheimer's, diabetes, and liver fibrosis. Nrf2 is one of the most studied biomarkers because of its essential role in providing neuroprotective effects.…”

Section: Discussionmentioning

confidence: 99%

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Quercetin Exerts a Protective Effect on Ischemic Stroke-induced Memory Deficits in Mice

Ardianto,

Lestari,

Primadani

et al. 2023

Journal of Pharmacology and Pharmacotherapeutics

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Objective Brain injury resulting from an ischemic stroke affects cognitive performance by disrupting the hippocampus. Several processes are involved in brain injury progression, including inflammation, glutamate excitotoxicity, and modulated brain peptide systems such as the melanocortin system. Reports show that quercetin exerts neuroprotective activity. This study investigates quercetin’s role in the cognitive function of ischemic stroke-induced mice and the possible mechanisms involved. Method ICR mice were used. The left unilateral common carotid artery occlusion was conducted for 4 h to induce an ischemic stroke in the mice. Quercetin 50, 100, and 200 mg/kg were administered to separate groups intraperitoneally for 7 days. Cognitive function was examined using the T-maze test. The hippocampal mRNA expressions of NR2A, NR2B, melanocortin 4 receptor (MC4R), pro-opiomelanocortin precursors (POMC), and nuclear factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction. Results It was found that stroke disrupted cognitive function. Quercetin administration ameliorated cognitive impairment. Quercetin attenuated the stroke-induced decrease in MC4R mRNA expression. Moreover, quercetin suppressed the stroke-induced increase in the hippocampal mRNA expression of NR2A. Conclusion Quercetin ameliorates cognitive deficits and normalizes impaired hippocampal melanocortin and glutamatergic signaling in ischemic stroke-induced mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quercetin Exerts a Protective Effect on Ischemic Stroke-induced Memory Deficits in Mice

Ardianto,

Lestari,

Primadani

et al. 2023

Journal of Pharmacology and Pharmacotherapeutics

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“…However, 100 μM propofol had no significant effect on mitophagy (Figures 5(a It is recognized that the cellular ROS homeostasis is modulated by their synthesis, mainly through NADPH oxidase complex, and their scavenging through the antioxidant machinery with glutathione and ascorbate acting as major antioxidants. Among multiple antioxidant enzymes, SOD, HO-1, and NQO1 were extensively studied in hippocampal neurons and neurological disorders [25,[51][52][53][54]. SOD is a group of metal-containing enzymes that catalyze the dismutation of superoxide radicals to molecular oxygen and hydrogen peroxide, providing cellular defense against reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

Zhang

Song

Ding

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Neuroinflammation-induced phosphorylated Tau (p-Tau) deposition in central nervous system contributes to neurodegenerative disorders. Propofol possesses neuroprotective properties. We investigated its impacts on tumor necrosis factor-α (TNF-α)-mediated p-Tau deposition in neurons. Methods. Mouse hippocampal neurons were exposed to propofol followed by TNF-α. Cell viability, p-Tau, mitophagy, reactive oxygen species (ROS), NOD-like receptor protein 3 (NLRP3), antioxidant enzymes, and p62/Keap1/Nrf2 pathway were investigated. Results. TNF-α promoted p-Tau accumulation in a concentration- and time-dependent manner. TNF-α (20 ng/mL, 4 h) inhibited mitophagy while increased ROS accumulation and NLRP3 activation. It also induced glycogen synthase kinase-3β (GSK3β) while inhibited protein phosphatase 2A (PP2A) phosphorylation. All these effects were attenuated by 25 μM propofol. In addition, TNF-α-induced p-Tau accumulation was attenuated by ROS scavenger, NLRP3 inhibitor, GSK3β inhibitor, or PP2A activator. Besides, compared with control neurons, 100 μM propofol decreased p-Tau accumulation. It also decreased ROS and NLRP3 activation, modulated GSK3β/PP2A phosphorylation, leaving mitophagy unchanged. Further, 100 μM propofol induced p62 expression, reduced Keap1 expression, triggered the nuclear translocation of Nrf2, and upregulated superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) expression, which was abolished by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Consistently, the inhibitory effect of 100 μM propofol on ROS and p-Tau accumulation was mitigated by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Conclusions. In hippocampal neurons, TNF-α inhibited mitophagy, caused oxidative stress and NLRP3 activation, leading to GSK3β/PP2A-dependent Tau phosphorylation. Propofol may reduce p-Tau accumulation by reversing mitophagy and oxidative stress-related events. Besides, propofol may reduce p-Tau accumulation by modulating SOD and HO-1 expression through p62/Keap1/Nrf2 pathway.

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“…ATP concentration was measured in cortical neurons transfected with GFP, GFP-T4, and GFP-T4C3 in the total lysates using a luciferin/luciferase bioluminescence assay kit (ATP determination kit #A22066, Molecular Probes, Invitrogen) [38]. The amount of ATP in each sample was calculated from standard curves and normalized to the total protein concentration.…”

Section: Measurement Of Atp Concentrationmentioning

confidence: 99%

Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is characterized by memory and cognitive impairment, accompanied by the accumulation of extracellular deposits of amyloid β-peptide (Aβ) and the presence of neurofibrillary tangles (NFTs) composed of pathological forms of tau protein. Mitochondrial dysfunction and oxidative stress are also critical elements for AD development. We previously showed that the presence of caspase-3 cleaved tau, a relevant pathological form of tau in AD, induced mitochondrial dysfunction and oxidative damage in different neuronal models. Recent studies demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a significant role in the antioxidant response promoting neuroprotection. Here, we studied the effects of Nrf2 activation using sulforaphane (SFN) against mitochondrial injury induced by caspase-3 cleaved tau. We used immortalized cortical neurons to evaluate mitochondrial bioenergetics and ROS levels in control and SFN-treated cells. Expression of caspase-3 cleaved tau induced mitochondrial fragmentation, depolarization, ATP loss, and increased ROS levels. Treatment with SFN for 24 h significantly prevented these mitochondrial abnormalities, and reduced ROS levels. Analysis of Western blots and rt-PCR studies showed that SFN treatment increased the expression of several Nrf2-related antioxidants genes in caspase-3 cleaved tau cells. These results indicate a potential role of the Nrf2 pathway in preventing mitochondrial dysfunction induced by pathological forms of tau in AD.

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Activation of the Melanocortin-4 Receptor Prevents Oxidative Damage and Mitochondrial Dysfunction in Cultured Hippocampal Neurons Exposed to Ethanol

Cited by 14 publications

References 68 publications

Quercetin Exerts a Protective Effect on Ischemic Stroke-induced Memory Deficits in Mice

Quercetin Exerts a Protective Effect on Ischemic Stroke-induced Memory Deficits in Mice

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease

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