Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest - 19/12/20
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Highlights |
• | Enhancement of central norepinephrine synthesis and norepinephrinergic neurotransmission can prevent S-IRA and SUDEP. |
• | Atomoxetine-mediated reduction of S-IRA was significantly reversed by prazosin without affecting cardiovascular function as a selective norepinephrine (NE) reuptake inhibitor. |
• | The reversal of atomoxetine-induced suppression of S-IRA by prazosin has no effects on seizure behavior without suppressing EEG activity. |
• | The enzyme activity of TH in the lower brainstem plays a key role in the pathogenesis of S-IRA and SUDEP. |
Abstract |
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central norepinephrine α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism. We examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained from using the PTZ-evoked SUDEP model. In our models, atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice, which makes the dying DBA/1 mice suffering from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug suppressed EEG activity. These data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributed to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.
El texto completo de este artículo está disponible en PDF.Keywords : Sudden unexpected death in epilepsy, Prazosin, Norepinephrine, Norepinephrine receptors, Tyrosine hydroxylase
Esquema
Vol 133
Artículo 111024- janvier 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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