Melatonin ameliorates hippocampal nitric oxide production and large conductance calcium‐activated potassium channel activity in chronic intermittent hypoxia

Abstract

Melatonin protects against hippocampal injury induced by intermittent hypoxia (IH). IH-induced oxidative stress is associated with decreases in constitutive production of nitric oxide (NO) and in the activity of large conductance calcium-activated potassium (BK) channels in hippocampal neurons. We tested the hypothesis that administration of melatonin alleviates the NO deficit and impaired BK channel activity in the hippocampus of IH rats. Sprague-Dawley rats were injected with melatonin (10 mg/kg, i.p.) or vehicle before daily IH exposure for 8 hr for 7 days. The NO and intracellular calcium ([Ca2+]i) levels in the CA1 region of hippocampal slices were measured by electrochemical microsenor and spectrofluorometry, respectively. The activity of BK channels was recorded by patch-clamping electrophysiology in dissociated CA1 neurons. Malondialdehyde levels were increased in the hippocampus of hypoxic rats and were lowered by the melatonin treatment. Levels of NO under resting and hypoxic conditions, and the protein expression of neuronal NO synthase (nNOS) were significantly reduced in the CA1 neurons of hypoxic animals compared with the normoxic controls. These deficits were mitigated in the melatonin-treated hypoxic rats with an improved [Ca2+]i response to acute hypoxia. The open probability of BK channels was decreased in the hypoxic rats and was partially restored in the melatonin-treated animals, without alterations in the expression of channel subunits and unitary conductance. Acute treatment of melatonin had no significant effects on the BK channel activity or on the [Ca2+]i response to hypoxia. Collectively, these results suggest that melatonin ameliorates the constitutive NO production and BK channel activity via an antioxidant mechanism against an IH-induced down-regulation of nNOS expression in hippocampal neurons.

Hypoxia. 4. Hypoxia and ion channel function

“…In this model, reduced expression of neuronal NO synthase, lower NO production, and limited hypoxia-induced elevations in [Ca 2ϩ ] i were also described (219), all of which can contribute to decreased K Ca channel activity. Additionally, increased ROS production following prolonged IH exposure (186,219,228) represents another possible pathway by which K Ca channel function might be reduced (190,220). These results suggest that early longterm IH exposure could have a detrimental impact on cognitive function.…”

“…It has been shown recently that pharmacological inactivation of K Ca channels leads to learning impairment (143), and deficits in learned behavior have also been described in rodents after 14 days of IH (243). It is perhaps not surprising then, that exposure of adult rat hippocampal neurons to IH for several days decreased the activity of K Ca channels (219,220). In this model, reduced expression of neuronal NO synthase, lower NO production, and limited hypoxia-induced elevations in [Ca 2ϩ ] i were also described (219), all of which can contribute to decreased K Ca channel activity.…”

Characteristics of single large-conductance Ca2+-activated K+ channels and their regulation of action potentials and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus

“…It has been reported that CIH markedly decreased open probability of BK channels in the CA1 pyramidal neurons which may account for the hippocampal injury in patients with sleep apnea (64). Further, Tjong et al (65) demonstrated that administration of melatonin ameliorates CIH-induced deficits in the constitutive NO production and impaired BK channel activity, which may provide a potential therapeutic treatment of neuronal injury in sleep apnea patients. Since BK channels are not only voltageand Ca 2ϩ -dependent, but are also sensitive to oxygen levels (20,39), we speculate that CIH may impair BK channels in PCMNs, which may lead to excessive Ca 2ϩ influx, inducing cell death in the NA (72)(73)(74).…”

Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner

“…MTNR1A-EGFP signals were equally distributed throughout the cell membrane prior to melatonin stimulation (Fig. 3c Several functional responses to melatonin are mediated by the regulation of ion channels [34]. To establish a direct role for VPA on whole-cell currents, therefore, we turned to current clamp studies in Neura-2a cells (Fig.…”