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The Role of Brain Inflammation in Cardiovascular Consequences of Seizures: Implications for SUDEP

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Tuesday, April 28, 2015

Study Looks at When Seizures Impact the Cardiovascular System

Examining the molecular mechanisms involved in the cascade of events that lead to sudden unexpected death in epilepsy (SUDEP) can identify targets for potential interventions to reduce the fatal consequences of seizures. Observations of SUDEPs that have occurred in epilepsy monitoring units, as well as physiological recordings taken at the time of seizures, have shown that seizures, especially tonic-clonic seizures, can lead to profound disturbances in cardiovascular function. These disturbances include instability in heart rhythms and blood pressure through abnormal activation of the autonomic nervous system. In a study by AM Bhandare and colleauges, researchers hypothesize that this potentially deadly physiological activity occurs when seizure activity spreads to involve nuclei in the brainstem that control the cardiovascular system.

In this study, researchers examined how seizures may influence autonomic activity by recording simultaneous EEG, EKG, expired carbon dioxide, sympathetic nerve activity, and phrenic nerve activity, which controls breathing, in a rodent model of seizures. Specifically, they examined the role of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide that acts on several receptors in the brain to activate adenylate cyclase which influences excitatory neurotransmission and production of the cytokine IL-6, an anti-inflammatory molecule involved in the protection of neurons from seizure induced damage. 

What Was Found

  • After injection of the convulsant kainic acid, there is an increase in sympathetic nerve activity, blood pressure, and heart rate that occurs after the seizure has started. 
  • Administration of a PACAP receptor blocker prior to seizure induction worsened the cardiovascular effects of the seizure, including changes in the EKG that are associated with cardiac arrhythmia.
  • Treating the rats with minocycline and doxycycline, drugs that block the activation of microglia, the main inflammatory cell in the brain, also worsened sympathetic nervous system activity caused by seizures.
  • Interestingly, administration of PACAP did not block seizure-related cardiovascular changes.

Microglia have been implicated in protection from seizure-induced cell damage. These findings raise the interesting possibility that some SUDEPs may result from a  loss of protective function of inflammatory cells in the autonomic nuclei of the brainstem. Prior research has shown that repeated seizures in chronic epilepsy may cause activated microglia to transform from neuroprotective cells to cells that facilitate inflammation and neuronal injury (reviewed here). It is unknown how changes in the function of these inflammatory neurons relate to SUDEP risk but manipulation of the PACAP system and IL-6 mediated neuroprotection could be a novel treatment strategy to protect against SUDEP.

Authored by: Daniel Friedman MD | epilepsy.com SUDEP Editor on 4/2015

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