The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-α toxicity involves membrane melatonin receptors
- 25 January 2010
- journal article
- Published by Wiley in Journal of Pineal Research
- Vol. 48 (2), 157-169
- https://doi.org/10.1111/j.1600-079x.2009.00739.x
Abstract
Loss of motoneurons may underlie some of the deficits in motor function associated with the central nervous system (CNS) injuries and diseases. We tested whether melatonin, a potent antioxidant and free radical scavenger, would prevent motoneuron apoptosis following exposure to toxins and whether this neuroprotection is mediated by melatonin receptors. Exposure of VSC4.1 motoneurons to either 50 μm H2O2, 25 μm glutamate (LGA), or 50 ng/mL tumor necrosis factor‐alpha (TNF‐α) for 24 h caused significant increases in apoptosis, as determined by Wright staining and ApopTag assay. Analyses of mRNA and proteins showed increased expression and activities of stress kinases and cysteine proteases and loss of mitochondrial membrane potential during apoptosis. These insults also caused increases in intracellular free [Ca2+] and activities of calpain and caspases. Cells exposed to stress stimuli for 15 min were then treated with 200 nm melatonin. Post‐treatment of cells with melatonin attenuated production of reactive oxygen species (ROS) and phosphorylation of p38, MAPK, and JNK1, prevented cell death, and maintained whole‐cell membrane potential, indicating functional neuroprotection. Melatonin receptors (MT1 and MT2) were upregulated following treatment with melatonin. To confirm the involvement of MT1 and MT2 in providing neuroprotection, cells were post‐treated (20 min) with 10 μm luzindole (melatonin receptor antagonist). Luzindole significantly attenuated melatonin‐induced neuroprotection, suggesting that melatonin worked, at least in part, via its receptors to prevent VSC4.1 motoneuron apoptosis. Results suggest that neuroprotection rendered by melatonin to motoneurons is receptor mediated and melatonin may be an effective neuroprotective agent to attenuate motoneuron death in CNS injuries and diseases.Keywords
This publication has 52 references indexed in Scilit:
- Cranial irradiation‐induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatmentJournal of Pineal Research, 2008
- Melatonin combats molecular terrorism at the mitochondrial levelInterdisciplinary Toxicology, 2008
- Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stressJournal of Pineal Research, 2008
- Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cellsCancer, 2007
- Melatonin attenuates arsenite‐induced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of α‐synucleinJournal of Pineal Research, 2007
- Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal glandJournal of Pineal Research, 2005
- Sequential Caspase-2 and Caspase-8 Activation Upstream of Mitochondria during Ceramideand Etoposide-induced ApoptosisPublished by Elsevier BV ,2004
- Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti‐apoptotic effects of melatoninThe FASEB Journal, 2004
- Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily.Published by Elsevier BV ,1997
- 2[125I]iodomelatonin binding sites in spleens of guinea pigsLife Sciences, 1992