title: Antagonism of PACAP or microglia function worsens the cardiovascular consequences of kainic-acid-induced seizures in rats.
abstract: Seizures are accompanied by cardiovascular changes that are a major cause of sudden unexpected death in epilepsy (SUDEP). Seizures activate inflammatory responses in the cardiovascular nuclei of the medulla oblongata and increase neuronal excitability. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with autocrine and paracrine neuroprotective properties. Microglia are key players in inflammatory responses in the CNS. We sought to determine whether PACAP and microglia mitigate the adverse effects of seizure on cardiovascular function in a rat model of temporal lobe epilepsy. Kainic acid (KA)-induced seizures increased splanchnic sympathetic nerve activity by 97%, accompanied by increase in heart rate (HR) but not blood pressure (BP). Intrathecal infusion of the PACAP antagonist PACAP(6-38) or the microglia antagonists minocycline and doxycycline augmented sympathetic responses to KA-induced seizures. PACAP(6-38) caused a 161% increase, whereas minocycline and doxycycline caused a 225% and 215% increase, respectively. In intrathecal PACAP-antagonist-treated rats, both BP and HR increased, whereas after treatment with microglial antagonists, only BP was significantly increased compared with control. Our findings support the idea that PACAP and its action on microglia at the level of the spinal cord elicit cardioprotective effects during seizure. However, intrathecal PACAP did not show additive effects, suggesting that the agonist effect was at maximum. The protective effect of microglia may occur by adoption of an M2 phenotype and expression of factors such as TGF-β and IL-10 that promote neuronal quiescence. In summary, therapeutic interventions targeting PACAP and microglia could be a promising strategy for preventing SUDEP.
authors: Australian School of Advanced Medicine, Macquarie University, Sydney, 2109 New South Wales, Australia, The Heart Research Institute, 2042 New South Wales, Australia, and.
authors: Amol M
authors: http://orcid.org/0000-0002-5214-9355
authors: AM
authors: Bhandare
authors: The Heart Research Institute, 2042 New South Wales, Australia, and.
authors: Suja
authors: S
authors: Mohammed
authors: The Heart Research Institute, 2042 New South Wales, Australia, and Department of Physiology, University of Sydney, Sydney, 2006 New South Wales, Australia paul.pilowsky@hri.org.au.
authors: Paul M
authors: http://orcid.org/0000-0003-3500-467X
authors: PM
authors: Pilowsky
authors: Australian School of Advanced Medicine, Macquarie University, Sydney, 2109 New South Wales, Australia, The Heart Research Institute, 2042 New South Wales, Australia, and.
authors: Melissa M J
authors: MM
authors: Farnham
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D001794:Blood Pressure; D004318:Doxycycline / Q000633:toxicity; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate; D008297:Male; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D008911:Minocycline; D004318:Doxycycline
keywords: PACAP; SUDEP; kainic acid; microglia; seizure; sympathetic nerve activity
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