Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment

Abstract

Background Anesthetic isoflurane has been reported to induce caspase-3 activation. The underlying mechanism(s) and targeted intervention(s), however, remain largely to be determined. Vitamin C (VitC) inhibits oxidative stress and apoptosis. We therefore employed VitC to further determine the up-stream mechanisms and the down-stream consequences of the isoflurane-induced caspase-3 activation. Methods H4 human neuroglioma cells over expressed human amyloid precursor protein (H4-APP cells) and rat neuroblastoma cells were treated either with: 1) 2% isoflurane or 2) the control condition, plus saline or 400 mM VitC for three or six hours. Western blot analysis and fluorescence assay was utilized at the end of the experiments to determine caspase-3 activation, levels of reactive oxygen species and ATP, and mitochondrial function. The interaction of isoflurane (1.4% for two hours) and VitC (80 mg/kg) on cognitive function in mice was also assessed in the Fear Conditioning System. Results Here we show for the first time that the VitC treatment attenuated the isoflurane-induced caspase-3 activation. Moreover, VitC mitigated the isoflurane-induced increase in the levels of reactive oxygen species, opening of mitochondrial permeability transition pore, reduction in mitochondrial membrane potential, and the reduction in ATP levels in the cells. Finally, VitC ameliorated the isoflurane-induced cognitive impairment in the mice. Conclusion Pending confirmation from future studies, these results suggested that VitC attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. These findings would promote further research into the underlying mechanisms and targeted interventions of anesthesia neurotoxicity.

Immune Modulation by Volatile Anesthetics

“…In cultured H4 human neuroglioma cells, isoflurane was found to induce caspase-3 activation, cause mitochondrial dysfunction, promote ROS accumulation, induce apoptosis, and reduce cell viability. 114–116 Strategies to target these isoflurane-induced events have been demonstrated. 115,116 …”

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

“…Previous studies have shown that isoflurane, a commonly used inhalation anesthetic, may induce the neurotoxicity associated with Alzheimer’s disease (AD) neuropathogenesis, including accumulation of β-amyloid protein and phosphorylation of Tau protein [1–11], and cause neurobehavior deficits [9, 12–19]. However, it remains largely unknown whether isoflurane can also cause DNA damage.…”

Co-administration effects of α-lipoic acid and nucleo CMP on arousal and sensory cortical activity

“…In addition, deficiency in lipoic acid causes cognitive deficiency and deterioration in cerebral retention capacity with little effects on sensory-motor motivational capability thus, long-term insufficiency in glutathione linked enzymes lead to structural and functional neuronal dys-connectivity and impairment of cognitive function, also; lipoic acid improves working memory in rats that treated by lipoic acid for two weeks duration via modulation of glutamate NMDA receptors. 18 Vitamin C modulates brain neurotransmitter system mainly glutaminergic,dopaminergic, cholinergic and serotonergic that are linked in memory, learning and cognitive function, moreover ,vitamin C regarded as important cofactor in the synthesis and releasing of noradrenaline and cerebral acetylcholine 19 ,this may explained the cognitive enhancing effects of lipoic acid that augments endogenous cerebral ascorbate level in aged and healthy subjects also , neurobehavioral effect of different herbs was explained depending on their antioxidant properties . 20 Animal model study showed that mice deficient in gene encoding for vitamin C lactone oxidase developed a sever cognitive impairment due to oxidative stress that measured by F4-neuroprostans, also, vitamin C reverses and attenuate scopolamine induced cognitive impairment in rats due to stimulation of central acetylcholineastrase enzyme at median forebrain bundle or through activation of cholinergic neurons, and in spite of vitamin C does not cross blood brain barrier, 21,22 therefore ,oral and intraperitoneal administration of vitamin C will not elevates cerebral ascorbate level ,but lipoic acid elevate brain ascorbate concentration that be able for central arousal effects which improve attention and learning due to modulation of hippocampal and forebrain glutamate concentration.…”