title: Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus.
abstract: BACKGROUND
  Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action.
  
  
  RESULTS
  In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses.
  
  
  CONCLUSIONS
  We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47(phox) phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE.
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Tsai
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
authors.forename: Kuei-sen
authors.initials: KS
authors.lastname: Hsu
authors.forename: Alice Y W
authors.initials: AY
authors.lastname: Chang
authors.forename: Samuel H H
authors.initials: SH
authors.lastname: Chan
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001933:Brain Stem; D019208:Brain-Derived Neurotrophic Factor; D002319:Cardiovascular System / Q000378:metabolism* / Q000503:physiopathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism; D013113:Spin Labels; D013226:Status Epilepticus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D013481:Superoxides / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013113:Spin Labels; D013481:Superoxides; D030421:Peroxynitrous Acid; C056165:acetovanillone; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020813:Receptor, trkB; D019808:Losartan; C001803:tempol