Oxidative stress in rat hippocampus caused by pilocarpine-induced seizures is reversed by buspirone

Freitas, Rizângela Lyne Mendes de; Santos, Ítala Mônica de Sales; Souza, Geane Felix de; Tomé, Adriana da Rocha; Saldanha, Gláucio Barros; Freitas, Rivelilson Mendes de

doi:10.1016/j.brainresbull.2009.09.014

Cited by 42 publications

(22 citation statements)

References 38 publications

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“…Unexpectedly, pilocarpine, but not carbachol, induced a concentration and time dependent loss in viability that was manifested by caspase activation and oxidative stress. Interestingly, this mode of cell death is also associated with the neuronal cell loss mediated by pilocarpine induced seizures in a rat model of epilepsy [44,67]. Similarly, the sustained activation of S6K and S6 induced by pilocarpine in SK-N-SH cells is consistent with evidence that aberrant mTOR expression contributes to pilocarpine induced seizures [20].…”

Section: Discussionmentioning

confidence: 64%

Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells

Edelstein¹,

Hao²,

Cao³

et al. 2011

Cellular Signalling

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Muscarinic acetylcholine receptors (mAchRs) are guanosine nucleotide-binding protein (G protein) coupled receptors that crosstalk with receptor tyrosine kinases (RTKs) to signal mitogenic pathways. In particular, mAchRs are known to couple with RTKs for several growth factors to activate the mammalian target of rapamycin (mTOR)/Akt pathway, a regulator of protein synthesis. The RTK for the vascular endothelial growth factor (VEGF), VEGFR2, can signal protein synthesis but whether it cooperates with mAchRs to mediate mTOR activation has not been demonstrated. Using serum starved SK-N-SH neuroblastoma cells, we show that the muscarinic receptor agonists carbachol and pilocarpine enhance the activation of mTOR substrates p70 S6 Kinase (S6K) and its target ribosomal protein S6 (S6) in a VEGFR2 dependent manner. Treatments with carbachol increased VEGFR2 phosphorylation, suggesting that mAchRs stimulate VEGFR2 transactivation to enhance mTOR signaling. Inhibitor studies revealed that phosphoinositide 3 kinase resides upstream from S6K, S6 and Akt phosphorylation while protein kinase C (PKC) functions in an opposing fashion by positively regulating S6K and S6 phosphorylation and suppressing Akt activation. Treatments with the phosphatase inhibitors sodium orthovanadate and okadaic acid increase S6, Akt and to a lesser extent S6K phosphorylation, indicating that tyrosine and serine/threonine dephosphorylation also regulates their activity. However, okadaic acid elicited a far greater increase in phosphorylation, implicating phosphatase 2A as a critical determinant of their function. Finally, pilocarpine but not carbachol induced a time and dose dependent cell death that was associated with caspase activation and oxidative stress but independent of S6K and S6 activation through VEGFR2. Accordingly, our findings suggest that mAchRs crosstalk with VEGFR2 to enhance mTOR activity but signal divergent effects on survival through alternate mechanisms.

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Section: Discussionmentioning

confidence: 64%

Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells

Edelstein¹,

Hao²,

Cao³

et al. 2011

Cellular Signalling

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“…5-HT1A receptor stimulation has been shown to lead to increased expression of several components of the antioxidant defense system, including SOD and catalase [44], [45], [46], anti-apoptotic proteins from the prosurvival members of the BCL family (e.g., Bcl-2 and Bcl-XL) [47], [48] and inhibitors of apoptosis proteins (e.g., Bax, XIAP) [47], [48], [49]. Similarly, we have shown that SOD2 is upregulated together with a decrease in the GSH/GSSG ratio in ARPE-19 cells by 5-HT 1A receptor activation.…”

Section: Discussionmentioning

confidence: 99%

The 5HT1a Receptor Agonist 8-Oh DPAT Induces Protection from Lipofuscin Accumulation and Oxidative Stress in the Retinal Pigment Epithelium

et al. 2012

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Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT1A receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT1A receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS-derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 µM H2O2 was assessed. 8-OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to the oxidized form of glutathione in H2O2-treated cells compared to controls and protected against H2O2-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT1A agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT1A receptor agonists may have potential as therapeutic agents in the treatment of retinal degenerative disease.

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“…5-HT 1A receptor agonists have also neuroprotective effects in animal models including central nervous system ischemia (Saruhashi et al, 2002, Mauler & Horvath, 2005, Ramos et al, 2004, Kukley et al, 2001, Torup et al, 2000, Piera et al, 1995, acute subdermal hematoma (Fournier et al, 1993), traumatic brain injury (Alessandri et al, 1999, Kline et al, 2002, excitotoxicity (Oosterink et al, 2003, Cosi et al, 2005, a Parkinson's disease model animal induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Bibbiani et al, 2001, Bezard et al, 2006, and sciatic nerve crush (Fournier et al, 1993). Additionally, it was reported that the 5-HT 1A agonists delayed the progression of motor neuron degeneration in pmn mice (Duong et al, 1998) and reduced lipid peroxidation in a rat epilepsy model (de Freitas et al, 2010). Such neuroprotective effects are considered to be caused by neuronal membrane hyperpolarization via G protein-coupled K + channels, decreasing glutamate release, blocking Ca 2+ channels or Na + channels, activation of MAPK (mitogen-actiated protein kinase)/ERK (extracellular signal-regulated kinase) signalling pathway resulting expression of anti-apoptotic proteins and inhibition of caspase, and an expression of brain derived neurotrophic factor (BDNF) mRNA, S100β and nerve growth factor.…”

Section: Tandospironementioning

confidence: 99%

Clinical Application of Drug Delivery Systems for Treating AMD

Kuno¹,

Fujii²

2012

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Oxidative stress in rat hippocampus caused by pilocarpine-induced seizures is reversed by buspirone

Cited by 42 publications

References 38 publications

Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells

Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells

The 5HT1a Receptor Agonist 8-Oh DPAT Induces Protection from Lipofuscin Accumulation and Oxidative Stress in the Retinal Pigment Epithelium

Clinical Application of Drug Delivery Systems for Treating AMD

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