Pallab Bhattacharya1, Anand Kumar Pandey2, Sudip Paul3, Ranjana Patnaik2. 1. 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. 2. School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, UP, India. 3. 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.
Abstract
AIM: 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. MATERIALS AND 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. KEY FINDINGS: 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. SIGNIFICANCE: Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.
AIM: 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 strokepatients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection. MATERIALS AND 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. KEY FINDINGS: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. SIGNIFICANCE: Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.
Authors: Brandon P Lucke-Wold; Ryan C Turner; Aric F Logsdon; James W Simpkins; Daniel L Alkon; Kelly E Smith; Yi-Wen Chen; Zhenjun Tan; Jason D Huber; Charles L Rosen Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472
Authors: Leonardo Lorente; María M Martín; Pedro Abreu-González; Antonia Pérez-Cejas; Luis Ramos; Mónica Argueso; Jordi Solé-Violán; Juan J Cáceres; Alejandro Jiménez; Victor García-Marín Journal: J Int Med Res Date: 2018-05-30 Impact factor: 1.671