ABSTRACT
In the present study we investigate the effect of Withania somnifera (WS) root extract and Withanolide A (WA) in restoring spatial memory deficit by inhibiting oxidative stress induced alteration in glutamergic neurotransmission. We demonstrate significant cellular loss in hippocampus of epileptic rats, visualized through decreased TOPRO stained neurons. Impaired spatial memory was observed in epileptic rats after Radial arm maze test. Treatment with WS and WA has resulted in increased number of TOPRO stained neurons. Enhanced performance of epileptic rats treated with WS and WA was observed in Radial arm maze test. The antioxidant activity of WS and WA was studied using superoxide dismutase (SOD) and Catalase (CAT) assays in the hippocampus of experimental rats. The SOD activity and CAT activity decreased significantly in epileptic group, treatment with WS and WA significantly reversed the enzymatic activities to near control. Real time gene expression studies of SOD and GPx showed significant up-regulation in epileptic group compared to control. Treatment with WS and WA showed significant reversal to near control. Lipid peroxidation quantified using TBARS assay, significantly increased in epileptic rats. Treatment with WS and WA showed significant reversal to near control. NMDA receptor expression decreased in epileptic rats. The treatment with WS and WA resulted in physiological expression of NMDA receptors. This data suggests that oxidative stress effects membrane constitution resulting in decreased NMDA receptor density leading to impaired spatial memory. Treatment with WS and WA has ameliorated spatial memory deficits by enhancing antioxidant system and restoring altered NMDA receptor density.
Subject(s)
Epilepsy, Temporal Lobe/psychology , Memory Disorders/drug therapy , Memory Disorders/psychology , Oxidative Stress/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Space Perception/drug effects , Withania/chemistry , Withanolides/pharmacology , Animals , Catalase/metabolism , Cognition Disorders/etiology , Cognition Disorders/prevention & control , Cognition Disorders/psychology , Dizocilpine Maleate/pharmacology , Epilepsy, Temporal Lobe/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Transporter 1/metabolism , Hemostasis/physiology , Immunohistochemistry , Male , Maze Learning/drug effects , Memory Disorders/etiology , Plant Roots/chemistry , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
Molecular processes regulating brain stem serotonergic receptors play an important role in the control of respiration. We evaluated 5-HT(2A) receptor alterations in the brain stem of neonatal rats exposed to hypoxic insult and the effect of glucose, oxygen, and epinephrine resuscitation in ameliorating these alterations. Hypoxic stress increased the total 5-HT and 5-HT(2A) receptor number along with an up regulation of 5-HT Transporter and 5-HT(2A) receptor gene in the brain stem of neonates. These serotonergic alterations were reversed by glucose supplementation alone and along with oxygen to hypoxic neonates. The enhanced brain stem 5-HT(2A) receptors act as a modulator of ventilatory response to hypoxia, which can in turn result in pulmonary vasoconstriction and cognitive dysfunction. The adverse effects of 100% oxygenation and epinephrine administration to hypoxic neonates were also reported. This has immense clinical significance in neonatal care.
Subject(s)
Brain Stem/metabolism , Epinephrine/pharmacology , Glucose/pharmacology , Hypoxia/metabolism , Oxygen/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Resuscitation , Animals , Animals, Newborn , Binding, Competitive , Epinephrine/therapeutic use , Glucose/therapeutic use , Hypoxia/drug therapy , Hypoxia, Brain/drug therapy , Hypoxia, Brain/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Ketanserin/pharmacology , Maze Learning , Memory , Oxygen/therapeutic use , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A/genetics , Serotonin/pharmacology , Serotonin 5-HT2 Receptor Agonists/pharmacology , Serotonin Antagonists/pharmacology , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Transcription, GeneticABSTRACT
Neonatal hypoxia induces brain injury through alterations in neurotransmitters and its receptors. Molecular processes regulating serotonergic receptors play an important role in the control of respiration under hypoxia. The present study evaluates the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT(2A) receptors and its transporter in the cerebral cortex of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine. Hypoxic stress increased total 5HT and 5HT(2A) receptor number along with an upregulation of 5HT(2A) receptor and 5HT transporter gene in the cortex. The enhanced cortical 5HT(2A) receptors may act as a modulator of ventilatory response to hypoxia. These alterations were reversed to near control by glucose supplementation. Glucose supplementation helped in managing the serotonergic functional alterations. Hypoxia-induced adenosine triphosphate depletion causes a reduction in blood glucose levels which can be encountered by glucose administration, and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia.
