Bhandare, Amol M., Kapoor, Komal, Powell, Kim L., Braine, Emma, Casillas-Espinosa, Pablo, O'Brien, Terence J., Farnham, Melissa M. J. and Pilowsky, Paul M. (2017) Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy. Neuroscience, 350 . pp. 23-38. ISSN 0306-4522.
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Abstract
The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti- inflammatory effects in the CNS. During acute seizures in rats, PACAP and microglia produce sympathoprotective effect at the intermediolateral cell column (IML), whereas their action on the presympathetic rostral ventrolateral medulla (RVLM) neurons mediates proarrhythmogenic changes. We evaluated the effect of PACAP and microglia at the IML on sympathetic nerve activity (SNA), cardiovascular reflex responses, and electrocardiographic changes in the post-status epilepticus (SE) model of acquired epilepsy, and control rats. Chronic spontaneous seizures in rats produced tachycardia with profound proarrhythmogenic effects (prolongation of QT interval). Antagonism of microglia, but not PACAP, significantly reduced the SNA and the corrected QT interval in post-SE rats. PACAP and microglia antagonists did not change baroreflex and peripheral or central chemoreflex responses with varied effect on somatosympathetic responses in post-SE and control rats. We did not notice changes in microglial morphology or changes in a number of M2 phenotype in epileptic nor control rats in the vicinity of RVLM neurons. Our findings establish that microglial activation, and not PACAP, at the IML accounts for higher SNA and proarrhythmogenic changes during chronic epilepsy in rats. This is the first experimental evidence to support a neurotoxic effect of microglia during chronic epilepsy, in contrast to their neuroprotective action during acute seizures.
| Item Type: | Journal Article |
|---|---|
| Alternative Title: | |
| Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
| Library of Congress Subject Headings (LCSH): | Epilepsy -- Mortality, Sudden death, Microglia, Rats, Polypeptides |
| Journal or Publication Title: | Neuroscience |
| Publisher: | Elsevier |
| ISSN: | 0306-4522 |
| Official Date: | 14 May 2017 |
| Dates: | Date Event 14 May 2017 Published 18 March 2017 Available 7 March 2017 Accepted |
| Volume: | 350 |
| Page Range: | pp. 23-38 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| Date of first compliant deposit: | 6 April 2017 |
| Date of first compliant Open Access: | 18 March 2018 |
| Funder: | Australian Research Council (ARC), National Health and Medical Research Council (Australia) (NHMRC) , Heart Research Institute, Macquarie University, University of Sydney |
| Grant number: | DE120100992, 1024489, 1065485, 1082215 and 1082215, 2012219 and 2012112 |
| RIOXX Funder/Project Grant: | Project/Grant ID RIOXX Funder Name Funder ID |
| URI: | https://wrap.warwick.ac.uk/87504/ |
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