u-0126 and Cognitive-Dysfunction

Type 1 diabetic animal models, generated by injecting streptozotocin (STZ), have been widely used in research. We previously reported that juvenile-onset diabetes mellitus (JDM) rats, which were prepared by administering STZ to 17-day-old rats, developed cognitive impairments and hippocampal synaptic plasticity deficiencies, which were restored by glucagon-like peptide-1 (GLP-1). GLP-1 and GLP-2 are simultaneously derived from proglucagon and act through their own specific receptors. The present study was performed to investigate the potential of GLP-2 in JDM rats. The results obtained demonstrated that GLP-2 restored impairments in spatial working memory and hippocampal long-term depression (LTD) in JDM rats, and that the MEK1/2 inhibitor, U0126, inhibited this recovery. Therefore, GLP-2 has potential in the treatment of cognitive deficits in childhood-onset diabetes.

Topics: Animals; Behavior, Animal; Butadienes; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 2; Hippocampus; Long-Term Synaptic Depression; MAP Kinase Signaling System; Memory, Short-Term; Nitriles; Protein Kinase Inhibitors; Rats; Rats, Wistar; Spatial Memory

Multiple exposures to anesthesia in children may increase the risk of developing cognitive impairment. Sevoflurane is an anesthetic that is commonly used in children during surgery. Cyclin-dependent kinase (CDK) 5 is involved in the regulation of sevoflurane-induced cognitive dysfunction, but the mechanistic details remain unclear. The present study evaluated the mechanism by which CDK5 mediates sevoflurane-induced cognitive dysfunction in mice.. Hippocampal neurons were isolated from postnatal day 0 C57BL/6 mouse pups. Six-day-old wild-type mice were exposed to sevoflurane and then treated with the CDK5 inhibitor roscovitine. The effects on cognitive function were evaluated with the Morris water maze and neuronal damage in the hippocampus was assessed by immunohistochemical analysis.. CDK5 activation increased neuronal damage by inducing Tau/glycogen synthase kinase (GSK) 3β and suppressing extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor (PPAR)γ/cyclic AMP response element-binding protein (CREB) signaling following exposure to sevoflurane. CDK5 inhibition by roscovitine administration alleviated sevoflurane-induced neuronal damage and cognitive impairment.. Inhibiting CDK5 with roscovitine has neuroprotective effects against neuronal injury and cognitive dysfunction caused by sevoflurane anesthesia that are exerted via modulation of Tau/GSK3β and ERK/PPARγ/CREB signaling.

Topics: Animals; Apoptosis Regulatory Proteins; Butadienes; Caspase 3; Cells, Cultured; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase 5; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3 beta; Hippocampus; Maze Learning; Methyl Ethers; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Neurons; Nitriles; Phosphorylation; PPAR gamma; Purines; Roscovitine; Sevoflurane; Signal Transduction; tau Proteins