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 Ϯ 12.6% sympathoexcitation (p Յ 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.

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

“…Seizure activity is accompanied with increased sympathetic output, increased plasma noradrenaline levels, tachycardia and elevated blood pressure (Read et al, 2015;Bhandare et al, 2016a). However, our non-invasive blood pressure measurements and plasma catecholamine analysis did not reveal significant differences in MAP or plasma catecholamine levels interictally between epileptic and control rats.…”

“…During electrophysiology experiments, we did not observe spontaneous seizures, which suggest that there might not be increased PACAP levels in post-SE rats during electrophysiology recordings. However, expression of PACAP can be upregulated after-seizures during the chronic epilepsy, which could produce either neuroprotective or excitatory effect on sympathetic preganglionic neurons as shown previously (Farnham et al, 2008;Farnham et al, 2011;Bhandare et al, 2015;Bhandare et al, 2016b;Bhandare et al, 2016a).…”

“…Epilepsy affects about 50 million people worldwide (WHO, 2005); seizures can range from brief, barely noticeable loss of attention to major convulsions that affect the entire neuraxis. Epilepsy is associated with changes in autonomic functions, such as sympathovagal imbalance, sympathetic reflex dysfunction, tachycardia with concomitant arrhythmia or bradycardia with associated apnoea (Dütsch et al, 2006;Bateman et al, 2008;Ponnusamy et al, 2012;Massey et al, 2014;Powell et al, 2014b;Bhandare et al, 2015;Bhandare et al, 2016a). Seizure associated autonomic cardiorespiratory changes are well-documented and are thought to play an important role in a mechanism of sudden unexpected death in epilepsy (SUDEP) (Nei et al, 2004;Dlouhy et al, 2015).…”

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats

“…Systemic KA produces sympathoactivation with pressor response, tachycardia, and lengthening of QT interval; [3][4][5] it also reduces tidal volume and rhythmicity, and in some animals ultimately leads to sudden death due to laryngospasm. Systemic kainic acid (KA) is commonly used to induce seizure activity in rodents, usually status epilepticus followed by repeated shorter-lasting seizures over several hours.…”

“…Systemic kainic acid (KA) is commonly used to induce seizure activity in rodents, usually status epilepticus followed by repeated shorter-lasting seizures over several hours. Systemic KA produces sympathoactivation with pressor response, tachycardia, and lengthening of QT interval; [3][4][5] it also reduces tidal volume and rhythmicity, and in some animals ultimately leads to sudden death due to laryngospasm. 6,7 Two further hypotheses proposed to explain seizure-related apneas and fatal cardiorespiratory collapse are the following: (1) spreading depolarization (similar to spreading depression) propagating from the forebrain into the brainstem, demonstrated in several mouse models [8][9][10] ; and (2) laryngospasm triggered by gastric acid reflux (gastric acid reflux has been shown following systemic KA).…”