Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

Amol M Bhandare¹, Komal Kapoor², Kim L Powell³, Emma Braine⁴, Pablo Casillas-Espinosa⁵, Terence J O'Brien⁶, Melissa M J Farnham⁷, Paul M Pilowsky⁸

Affiliations

¹ Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address: bhandaream@gmail.com.
² Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia. Electronic address: contactkomalk@gmail.com.
³ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: kpowell@unimelb.edu.au.
⁴ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: ebraine@unimelb.edu.au.
⁵ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: pablo.casillas@unimelb.edu.au.
⁶ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: obrientj@unimelb.edu.au.
⁷ The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia. Electronic address: melissa.farnham@hri.org.au.
⁸ The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia. Electronic address: paul.pilowsky@hri.org.au.

PMID: 28323007
DOI: 10.1016/j.neuroscience.2017.03.012

Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

Amol M Bhandare et al. Neuroscience. 2017.

. 2017 May 14:350:23-38.

doi: 10.1016/j.neuroscience.2017.03.012. Epub 2017 Mar 18.

Authors

Amol M Bhandare¹, Komal Kapoor², Kim L Powell³, Emma Braine⁴, Pablo Casillas-Espinosa⁵, Terence J O'Brien⁶, Melissa M J Farnham⁷, Paul M Pilowsky⁸

Affiliations

¹ Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address: bhandaream@gmail.com.
² Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2109 New South Wales, Australia; The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia. Electronic address: contactkomalk@gmail.com.
³ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: kpowell@unimelb.edu.au.
⁴ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: ebraine@unimelb.edu.au.
⁵ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: pablo.casillas@unimelb.edu.au.
⁶ Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: obrientj@unimelb.edu.au.
⁷ The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia. Electronic address: melissa.farnham@hri.org.au.
⁸ The Heart Research Institute, 7 Eliza Street, Sydney 2042 New South Wales, Australia; Department of Physiology, University of Sydney, Sydney 2006 New South Wales, Australia. Electronic address: paul.pilowsky@hri.org.au.

PMID: 28323007
DOI: 10.1016/j.neuroscience.2017.03.012

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.

Keywords: PACAP; microglia; proarrhythmogenic; rats; sympathoexcitation; temporal lobe epilepsy.

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Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

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Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

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