Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate.

Glutamate excitotoxicity is involved in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer's disease, for which central insulin resistance is a comorbid condition. Neurotoxicity of glutamate (Glu) is primarily associated with hyperactivation of the ionotropic N-methyl-D-aspartate receptors (NMDARs), causing a sustained increase in intracellular free calcium concentration ([Ca]) and synchronous mitochondrial depolarization and an increase in intracellular superoxide anion radical (O) production. Recently, we found that insulin protects neurons against excitotoxicity by decreasing the delayed calcium deregulation (DCD).

Inhaled [D-Ala]-Dynorphin 1-6 Prevents Hyperacetylation and Release of High Mobility Group Box 1 in a Mouse Model of Acute Lung Injury.

COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus that can rapidly escalate to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). Recently, extracellular high mobility group box 1 (HMGB1) has been identified as an essential component of cytokine storms that occur with COVID-19; HMGB1 levels correlate significantly with disease severity. Thus, the modulation of HMGB1 release may be vital for treating COVID-19.

Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer's disease and other dementias, Parkinson's disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation.

Insulin Receptors and Intracellular Ca Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity.

Since the discovery of insulin and insulin receptors (IR) in the brain in 1978, numerous studies have revealed a fundamental role of IR in the central nervous system and its implication in regulating synaptic plasticity, long-term potentiation and depression, neuroprotection, learning and memory, and energy balance. Central insulin resistance has been found in diverse brain disorders including Alzheimer's disease (AD). Impaired insulin signaling in AD is evident in the activation states of IR and downstream signaling molecules.

Altered behaviour, dopamine and norepinephrine regulation in stressed mice heterozygous in TPH2 gene.

Gene-environment interaction (GxE) determines the vulnerability of an individual to a spectrum of stress-related neuropsychiatric disorders. Increased impulsivity, excessive aggression, and other behavioural characteristics are associated with variants within the tryptophan hydroxylase-2 (Tph2) gene, a key enzyme in brain serotonin synthesis. This phenotype is recapitulated in naïve mice with complete, but not with partial Tph2 inactivation.