Short Sustained, But Not Intermittent, Hypoxia Attenuates Kainic Acid‐Induced Sympathetic Nerve Activity Increase and Prevents Seizure Development in Rats
Authors: Nedoboy Polina E , Cohen Elizabeth M , Kakall Zohra M , Kim Seung Jae , O'Brien Terence J , Powell Kim L , Farnham Melissa MJ , Pilowsky Paul M 
Published: June 2021

The prevalence of obstructive sleep apnea (OSA), associated with intermittent hypoxia, in epileptic patients is higher than in the general population. Continuous positive airway pressure therapy improves seizure control in humans and preconditioning with mild hypoxia also results in the reduction of seizures. Here we sought to elucidate the effects of both detrimental (acute intermittent) and therapeutic (short sustained) forms of hypoxia on sympathetic nerve activity in the rat model of kainic acid‐induced epilepsy.

Methodology

urethane anesthetised, vagotomised, paralysed, artificially ventilated adult Sprague‐Dawley male rats were used. Rats were injected with 10 mg/kg of kainic acid (KA) IP to induce status epilepticus, or [volume] PBS IP (vehicle control). Thirty minutes after KA injection, rats were subjected to either 10 × 45s episodes of hypoxia (10% O2, 90% N2, acute intermittent hypoxia, AIH) with a 5min recovery period between each episode, or 7.5min of hypoxia (10% O2, 90% N2, short sustained hypoxia, SSH), or room air (Ctrl). Hippocampal EEG activity was continuously recorded, together with ECG, blood pressure and splanchnic sympathetic nerve activity (SNA).

Results

KA induced a gradual increase in the amplitude of gamma oscillations (25 – 50 Hz) in the hippocampus and invariably lead to status epilepticus within 60 – 90 min. A dramatic ~150% increase in SNA was observed by 210 min post‐KA injection. Each episode of AIH cause a brief (~1min) drop in the amplitude of gamma frequencies to below the baseline level, followed by a large increase in gamma range frequency after the 10th episode of AIH, and subsequent seizure activity. In addition, AIH treatment exacerbated the increase in SNA (200% from baseline). SSH treatment also suppressed EEG activity in the gamma range to below baseline for the duration of hypoxia (7.5 min), however, after the hypoxia exposure, oscillatory activity in the gamma range stabilised and no seizures occurred within the recorded timeframe. Importantly, SNA, although higher than in the control experiments, was significantly lower compared to KA treatment with room air and KA with AIH.

Conclusions

Exposure to a short sustained hypoxia appears to be protective against seizure development in the acute model of KA‐induced epilepsy in rats. This protective effect might be partially facilitated through the attenuation of KA‐induced sympathoexcitation. In contrast, acute intermittent hypoxia not only failed to prevent seizures, but significantly increased SNA. These findings provide new insights into the mechanisms of OSA‐facilitated seizure exacerbation in epilepsy, and highlights the potential protective effects of short sustained hypoxia.

Support or Funding Information

NHMRC grant #1082215

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.