minocycline and Arrhythmias--Cardiac

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.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Doxycycline; Epilepsy, Temporal Lobe; Heart; Heart Rate; Male; Microglia; Minocycline; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; Seizures; Spinal Cord; Sympathetic Nervous System

Minocycline has been shown to protect against myocardial ischemia-reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45mg/kg, i.p.) 1h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K(ATP)) channels] which were once injected 10min before ischemia and then subjected to ischemia for 30min. Ventricular arrhythmias were assessed. L-type Ca(2+) current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P<0.05). The duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P<0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias (P<0.05 for all). In addition, minocycline inhibited L-type Ca(2+) currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K(ATP) channels and L-type Ca(2+) channels may be involved.

Topics: Animals; Anti-Bacterial Agents; Arrhythmias, Cardiac; Calcium; Cell Membrane; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Male; Minocycline; Myocardial Ischemia; Phosphatidylinositol 3-Kinases; Phosphoproteins; Potassium Channels; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction