title: Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia.
abstract: OBJECTIVE
  Aquaporin-4(AQP4) expression in the brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection.
  
  
  METHODS
  An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5mg/kg, i.p. melatonin or placebo at 30 min prior, 60 min post and 120 min post 60 min of middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.
  
  
  RESULTS
  Melatonin at 60 min post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde (MDA) were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C (PKC) influenced AQP4 expression in the cerebral cortex and dorsal striatum.
  
  
  CONCLUSIONS
  Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.
authors: Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India. Electronic address: p.bhattacharya@med.miami.edu.
authors: Pallab
authors: P
authors: Bhattacharya
authors: School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India.
authors: Anand Kumar
authors: AK
authors: Pandey
authors: School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India; Department of Biomedical Engineering, North Eastern Hill University (NEHU), Shillong, 793022, Meghalaya, India.
authors: Sudip
authors: S
authors: Paul
authors: School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India.
authors: Ranjana
authors: R
authors: Patnaik
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051401:Aquaporin 4 / Q000378:metabolism*; D015153:Blotting, Western; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D000975:Antioxidants; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D018696:Neuroprotective Agents; D009573:Nitrites; D008315:Malondialdehyde; D011493:Protein Kinase C; D008550:Melatonin; D002118:Calcium
keywords: Aquaporin-4; Brain edema; Melatonin; Neuroprotection; Protein kinase C