Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy.
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.
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.
Amol M
AM
Bhandare
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.
Komal
K
Kapoor
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: kpowell@unimelb.edu.au.
Kim L
KL
Powell
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: ebraine@unimelb.edu.au.
Emma
E
Braine
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: pablo.casillas@unimelb.edu.au.
Pablo
P
Casillas-Espinosa
Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: obrientj@unimelb.edu.au.
Terence J
TJ
O'Brien
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.
Melissa M J
MMJ
Farnham
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.
Paul M
PM
Pilowsky
D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology
D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D008911:Minocycline
PACAP; microglia; proarrhythmogenic; rats; sympathoexcitation; temporal lobe epilepsy