Ameliorative effects of Coccinia grandis leaf extract on Diabetes-Induced alterations of glucose metabolism, Cox activity and histological changes in Brain of Wistar Rats

Coccinia grandis has been used in tribal populations of India both as food and medicine, but it has been not reported to be a neuroprotective agent yet. The present study was designed to evaluate the protective effects of Coccinia grandis leaf extract on diabetes induced brain damage of Wistar rats. This study reports the protective effect of methanolic leaf extract of Coccinia grandis against STZ induced diabetes in rats. Metformin (150mg/kg body wt.) was used as a reference drug. The enzymes of the polyol pathway and its related substrates were studied in the brain tissue. The effect of Coccinia on Cyclooxygenase (COX) and Prostaglandin peroxidise (PG) was also studied. Diabetes induced rats showed a significantly increased activity of Aldose reductase, Sorbitol dehydrogenase, Glucose-6-phosphodehydrogenase, whereas the decreased activity of Hexokinase. The content of Glucose, Sorbitol significantly increased in rat brain. Sodium potassium ATPase activity was also decreased in diabetic rats. COX, PG peroxidase was increased. Histological alternations were induced in the hippocampus of STZ treated diabetic rats. Oral administration of Coccinia leaf extract (200mg/kg) of body weight to diabetic rats for 21 days efficiently attenuated the parameters studied. A decreased activity of brain AR, sorbitol dehydrogenase, glucose-6-dehydrogenase was observed along with the increase in Hexokinase and Sodium potassium ATPase activity. It also showed decreased content of glucose and Sorbitol. Diabetes induced brain damage in the hippocampus and cerebral cortex was restored with Coccinia treatment. Decreased COX and PG peroxidase suggest its protection against inflammation. The current results suggest that Coccinia grandis leaf extract exerts the potential ability to reverse the progression of hyperglycemia and its concomitant induced brain damage.

ATP1A3 ‐Encoded Sodium‐Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia

Background Pathogenic variation in the ATP1A3 ‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status ( P <0.001) than in patients with genotype‐negative status, and significantly shorter in patients with the ATP1A3‐D801N variant than patients with other variants ( P <0.001). The mean QTc for ATP1A3‐D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

The Effect of Moringa Oleifera Methanol Leaves Extracts on Sodium/Potassium (Na+ /K+ ) Atpase in Streptozotocin-Induced Experimental Diabetic Albino Male Rat Models

Background: An evaluation of the effect of Moringa oleifera methanol leaves extracts on Sodium/Potassium ATPase xin streptozotocin-induced experimental diabetic albino male rats’ model.Methods: Q ualitative phytochemical analysis was carried out on the methanol extracts of M. oleifera leaves usingacceptable chemical methods. The LD50 of the plant extract was conducted and was non-lethal at 5000mg/kg. Thirty, albino male rats weighing 120g – 180g were arranged into five groups, comprising six rats per group. Parameters such as sodium/potassium ATPase (Na+/K+ ATPase), glycosylated hemoglobin (HbA1c), and fasting blood glucose levels were assayed.Results: M.oleifera methanol leaves extract (at 500mg/kg and 1000mg/kg) increased sodium/potassium -ATPase activities in an albino male rat induced with hyperglycemia. It was also observed that the extract at doses of 500mg/kg (132.67 + 8.14) and1000mg/kg (114.00 + 15.38) for fasting blood glucose, 500mg/kg (6.29 + 0.26) and1000mg/kg (6.08 + 0.26) for glycosylated haemoglobin (HbA1c) were effective in ameliorating diabetes induced bystreptozotocin.Conclusions: This study established that the decrease in the activity of sodium/potassium -ATPase in streptozotocininduced type II diabetes in albino male rats can be increased to normal functionality by oral administration of M. oleifera methanol leaves extracts at doses of 500mg/kg and 1000mg/kg.

A Case of Recurrent Paralysis and Low Potassium: Is It the Thyroid?

Introduction: Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism that is characterized by episodes of hypokalemia and acute weakness. Although hyperthyroidism is more common in females, over 95% of cases of TPP have been observed in males, especially in Asian males with an incidence of 2% among hyperthyroid patients. In non-Asian populations, the incidence in hyperthyroid patients is estimated to be around 0.1 to 0.2% [1]. We describe a case of TPP seen in a Hispanic male. Case Report: A 36-year-old Hispanic male with no past medical history presents with weakness in all extremities and difficulty breathing after consuming a carbohydrate heavy meal the night prior. He reports a recent, similar episode evaluated in another ER, which resolved after given potassium supplementation. He denied any vomiting, diarrhea, polyuria, diaphoresis, use of insulin or other medications, or any family history of paralysis. His labs were significant for hypokalemia of 1.9, TSH of &lt;0.005 (0.358-3.740), free T4 of 2.22 (0.76-1.46), and total T3 of 2.7 (0.60-1.81). Thyroid stimulating immunoglobulin was 0.12 (0.0-0.55). His symptoms improved and potassium levels normalized following the administration of potassium chloride. He was discharged on propranolol and advised to follow up for further workup of his hyperthyroidism with radioactive iodine uptake scan. Discussion: Thyrotoxic periodic paralysis is a potentially life-threatening condition associated with cardiac arrhythmias and respiratory failure. Hyperthyroidism increases response to β-adrenergic stimulation, which increases activity of the sodium-potassium ATPase and causes hyperpolarization of skeletal muscle [2]. Hyperthyroid patients are prone to episodes of paralysis due to their increased susceptibility to the hypokalemic action of insulin, which activates the sodium-potassium ATPase pump, and epinephrine, which stimulates β-adrenoreceptors. Management of an acute attack of TPP includes potassium administration. In cases where paralysis and hypokalemia are not reversed, intravenous propranolol has been shown to resolve the attack by blocking the β-adrenergic receptors. Definitive treatment of TPP includes managing the hyperthyroid state with medical therapy, radioactive iodine therapy, or surgery. Until the euthyroid state is reached, a β-blocker can prevent episodes of acute paralysis. Avoidance of carbohydrate heavy meals, exercise, and stress are recommended as these factors can potentially exacerbate hypokalemia. In patient with acute paralysis, it is important to consider the diagnosis of TPP as this condition can be prevented once euthyroidism is achieved. Diagnosis and management will lead to prevention of morbidity and mortality associated with the hypokalemia. References: 1.Vijayakumar A, et al. J Thyroid Res. 2014;2014:649502. 2.Layzer RB. Annals of Neurology. 1982;11(6):547–552.

Adenosine Receptor Modulation of Hypoxic-ischemic Injury in Striatum of Newborn Piglets

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of pediatric and adult mortality and morbidity. Unfortunately, to date, no effective treatment has been identified. In the striatum, neuronal injury is analogous to the cellular mechanism of necrosis observed during NMethyl- D-Aspartate (NMDA) excitotoxicity. Adenosine acts as a neuromodulator in the central nervous system, the role of which relies mostly on controlling excitatory glutamatergic synapses. Objective: To examine the effect of pretreatment of SCH58261, an adenosine 2A (A2A) receptor antagonist and modulator of NMDA receptor function, following hypoxic-ischemia (HI) on sodium- potassium ATPase (Na+, K+-ATPase) activity and oxidative stress. Methods: Piglets (4-7 days old) were subjected to 30 min hypoxia and 7 min of airway occlusion producing asphyxic cardiac arrest. Groups were divided into four categories: HI samples were divided into HI-vehicle group (n = 5) and HI-A2A group (n = 5). Sham controls were divided into Sham vehicle (n = 5) and Sham A2A (n = 5) groups. Vehicle groups were pretreated with 0.9% saline, whereas A2A animals were pretreated with SCH58261 10 min prior to intervention. Striatum samples were collected 3 h post-arrest. Sodium-potassium ATPase (Na+, K+-ATPase) activity, malondialdehyde (MDA) + 4-hydroxyalkenals (4-HDA) and glutathione (GSH) levels were compared. Results: Pretreatment with SCH58261 significantly attenuated the decrease in Na+, K+-ATPase, decreased MDA+4-HDA levels and increased GSH in the HI-A2A group when compared to HIvehicle. Conclusion: A2A receptor activation may contribute to neuronal injury in newborn striatum after HI in association with decreased Na+, K+-ATPase activity and increased oxidative stress.

Naked mole-rats suppress energy metabolism and modulate membrane cholesterol in chronic hypoxia

Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and β-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25–99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and β-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.