Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine

Abstract

Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressivelike brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1β, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure lead to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased I h currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and I h currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.

Dietary and metabolic risk of neuropsychiatric disorders: insights from animal models

“…In another study [56], after feeding mice a HFD (60% kcal from fat) for 15 weeks, anxiety-like behaviour and body weight increased, and glucose tolerance decreased in both female and male C57BL/6J mice. HFD (59% kcal from fat) exposure for 18 weeks led to glucose intolerance, anxiety/depression-like behaviour and neuroinflammation in male mice, with similar but non-significant trends in females [108]. Wu et al…”

“…A number of studies support the idea that HFD-induced neuropsychiatric disorders may be related to inflammatory responses in the brain [59,63,65,73,101,108], referred to as neuroinflammation, and to peripheral inflammatory responses [61,73]. Two animal models examining short-term HFD-induced depression-like behaviour noted increased serum inflammatory factors, including IL-6, IL-1β, TNFα and IL-6 [61,106].…”

“…Two animal models examining short-term HFD-induced depression-like behaviour noted increased serum inflammatory factors, including IL-6, IL-1β, TNFα and IL-6 [61,106]. Furthermore, a long-term HFD significantly increased the expression of pro-inflammatory cytokines (TNFα, IL-1β, IL-6, IL-2, and IL-17A) in the hippocampus, amygdala and prelimbic cortex [63,73,108] and downregulated the expression of anti-inflammatory cytokines (IL-10 and IL-4) in the hippocampus [73].…”

Ion-Channel Antiepileptic Drugs: An Analytical Perspective on the Therapeutic Drug Monitoring (TDM) of Ezogabine, Lacosamide, and Zonisamide

“…In the rat model, EZG reduced the stimulation of glutamate release and prevented the neuronal damage caused by 4-aminopyridine; however, it did not block its epileptic activity with equal effectiveness [48]. In mice, chronic high-fat-diet-induced neuroinflammation can be effectively treated by retigabine [49]. In the same animal, EZG attenuated focal cerebral ischemic injury, probably through reducing oxidative stress and mitochondria-mediated apoptosis via inhibition of protein phosphorylation by p38 and c-Jun N-terminal kinases (JNKs) [50].…”

Correction of disorders of neuronal homeostatic mechanisms in case of neuropsychiatric diseases as a probable direction of drug exposure

“…В то же время неселективный активатор Кv7 каналов К + антиконвульсант ретигабин нормализовал I h токи, возбудимость пирамидных нейронов прелимбической коры и устранял нарушения поведения. Следовательно, ретигабин может быть рекомендован для лечения резистентных к антидепрессантам форм депрессии [37].…”