title: Seizure-Induced Sympathoexcitation Is Caused by Activation of Glutamatergic Receptors in RVLM That Also Causes Proarrhythmogenic Changes Mediated by PACAP and Microglia in Rats.
abstract: Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures. Pituitary adenylate cyclase activating polypeptide (PACAP) is an excitatory neuropeptide with neuroprotective properties, whereas microglia are key players in inflammatory responses in CNS. We investigated the roles of glutamate, PACAP, and microglia on RVLM catecholaminergic neurons during the cardiovascular responses to 2 mg/kg kainic acid (KA)-induced seizures in urethane anesthetized, male Sprague Dawley rats. Microinjection of the glutamate antagonist, kynurenic acid (50 nl; 100 mM) into RVLM, blocked the seizure-induced 43.2 ± 12.6% sympathoexcitation (p ≤ 0.05), and abolished the pressor responses, tachycardia, and QT interval prolongation. PACAP or microglia antagonists (50 nl) (PACAP(6-38), 15 pmol; minocycline 10 mg/ml) microinjected bilaterally into RVLM had no effect on seizure-induced sympathoexcitation, pressor responses, or tachycardia but abolished the prolongation of QT interval. The actions of PACAP or microglia on RVLM neurons do not cause sympathoexcitation, but they do elicit proarrhythmogenic changes. An immunohistochemical analysis in 2 and 10 mg/kg KA-induced seizure rats revealed that microglia surrounding catecholaminergic neurons are in a "surveillance" state with no change in the number of M2 microglia (anti-inflammatory). In conclusion, seizure-induced sympathoexcitation is caused by activation of glutamatergic receptors in RVLM that also cause proarrhythmogenic changes mediated by PACAP and microglia.
  
  
  CONCLUSIONS
  Sudden unexpected death in epilepsy is a major cause of death in epilepsy. Generally, seizures are accompanied by changes in brain function leading to uncontrolled nerve activity causing high blood pressure, rapid heart rate, and abnormal heart rhythm. Nevertheless, the brain chemicals causing these cardiovascular changes are unknown. Chemicals, such as glutamate and pituitary adenylate cyclase activating polypeptide, whose expression is increased after seizures, act on specific cardiovascular nuclei in the brain and influence the activity of the heart, and blood vessels. Microglia, which manage excitation in the brain, are commonly activated after seizure and produce pro- and/or anti-inflammatory factors. Hence, we aimed to determine the effects of blocking glutamate, pituitary adenylate cyclase activating polypeptide, and microglia in the RVLM and their contribution to cardiovascular autonomic dysfunction in seizure.
authors.affiliation: The Heart Research Institute, Sydney 2042, New South Wales, Australia, Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109, New South Wales, Australia, and.
authors.forename: Amol M
authors.identifier: http://orcid.org/0000-0002-5214-9355
authors.initials: AM
authors.lastname: Bhandare
authors.affiliation: The Heart Research Institute, Sydney 2042, New South Wales, Australia, Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109, New South Wales, Australia, and.
authors.forename: Komal
authors.initials: K
authors.lastname: Kapoor
authors.affiliation: The Heart Research Institute, Sydney 2042, New South Wales, Australia, Department of Physiology, University of Sydney, Sydney 2006, New South Wales, Australia paul.pilowsky@hri.org.au.
authors.forename: Paul M
authors.identifier: http://orcid.org/0000-0003-3500-467X
authors.initials: PM
authors.lastname: Pilowsky
authors.affiliation: The Heart Research Institute, Sydney 2042, New South Wales, Australia, Department of Physiology, University of Sydney, Sydney 2006, New South Wales, Australia.
authors.forename: Melissa M J
authors.initials: MM
authors.lastname: Farnham
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018376:Cardiovascular Abnormalities / Q000209:etiology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D065818:Gamma Rhythm / Q000187:drug effects / Q000502:physiology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D013153:Splanchnic Nerves / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014628:Vagotomy
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D008840:Microfilament Proteins; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017470:Receptors, Glutamate; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D014446:Tyrosine 3-Monooxygenase; D008911:Minocycline; D007608:Kainic Acid
keywords: PACAP; glutamate; microglia; rat; seizure; sympathetic