sirolimus and Brain-Diseases

In hyperinsulinemic hypoglycemia (HH) there is dysregulation of insulin secretion from pancreatic β-cells. Insulin secretion becomes inappropriate for the level of blood glucose leading to severe hypoglycemia. HH is associated with a high risk of brain injury because insulin inhibits lipolysis and ketogenesis thus preventing the generation of alternative brain substrates (such as ketone bodies). Hence HH must be diagnosed as soon as possible and the management instituted appropriately to prevent brain damage. This article reviews the mechanisms of glucose physiology in the newborn, the mechanisms of insulin secretion, the etiologic types of HH, and its management.

Topics: Blood Glucose; Brain Diseases; Congenital Hyperinsulinism; Diagnostic Imaging; Genetic Testing; Humans; Immunosuppressive Agents; Infant, Newborn; Insulin; Insulin Secretion; Insulin-Secreting Cells; Pancreatectomy; Receptors, Glucagon; Sirolimus

Tuberous sclerosis complex is an autosomal dominant disease, with variable expressivity and multisystemic involvement, which is characterised by the growth of benign tumours called hamartomas. The organs that are most commonly affected are the brain, skin, kidneys, eyes, heart and lungs. Of all the children with this disease, 85% present neurological manifestations that, due to their severity, are the main cause of morbidity and mortality. The most significant neurological manifestations are epilepsy, autism spectrum disorders and mental retardation. It has been shown that in tuberous sclerosis complex the genes TSC1 and TSC2 alter the mTOR enzyme cascade, which sets off inhibition of this pathway. The possibility of resorting to treatments applied at the origin, thus inhibiting this pathway, is currently being evaluated.

Topics: Anticonvulsants; Astrocytoma; Autistic Disorder; Brain Diseases; Brain Neoplasms; Drug Design; Epilepsy; Everolimus; Glioma, Subependymal; Hamartoma; Humans; Intellectual Disability; Learning Disabilities; Molecular Targeted Therapy; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Diabetic encephalopathy, a severe complication of diabetes mellitus, is characterized by neuroinflammation and aberrant synaptogenesis in the hippocampus leading to cognitive decline. Mammalian target of rapamycin (mTOR) is associated with cognition impairment. Nuclear factor-κB (NF-κB) is a transcription factor of proinflammatory cytokines. Although mTOR has been ever implicated in processes occurring in neuroinflammation, the role of this enzyme on NF-κB signaling pathway remains unclear in diabetic encephalopathy. In the present study, we investigated whether mTOR regulates the NF-κB signaling pathway to modulate inflammatory cytokines and synaptic plasticity in hippocampal neurons. In vitro model was constructed in mouse HT-22 hippocampal neuronal cells exposed to high glucose. With the inhibition of mTOR or NF-κB by either chemical inhibitor or short-hairpin RNA (shRNA)-expressing lentivirus-vector, we examined the effects of mTOR/NF-κB signaling on proinflammatory cytokines and synaptic proteins. The diabetic mouse model induced by a high-fat diet combined with streptozotocin injection was administrated with rapamycin (mTOR inhibitor) and PDTC (NF-κB inhibitor), respectively. High glucose significantly increased mTOR phosphorylation in HT-22 cells. While inhibiting mTOR by rapamycin or shmTOR significantly suppressed high glucose-induced activation of NF-κB and its regulators IKKβ and IκBα, suggesting mTOR is the upstream regulator of NF-κB. Furthermore, inhibiting NF-κB by PDTC and shNF-κB decreased proinflammatory cytokines expression (IL-6, IL-1β, and TNF-α) and increased brain-derived neurotrophic factor (BDNF) and synaptic proteins (synaptophysin and PSD-95) in HT-22 cells under high glucose conditions. Besides, the mTOR and NF-κB inhibitors improved cognitive decline in diabetic mice. The inhibition of mTOR and NF-κB suppressed mTOR/NF-κB signaling pathway, increased synaptic proteins, and improved ultrastructural synaptic plasticity in the hippocampus of diabetic mice. Activating mTOR/NF-κB signaling pathway regulates the pathogenesis of diabetic encephalopathy, such as neuroinflammation, synaptic proteins loss, and synaptic ultrastructure impairment. The findings provide the implication that mTOR/NF-κB is potential new drug targets to treat diabetic encephalopathy.

Topics: Animals; Brain Diseases; Cell Line; Cell Survival; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Neuronal Plasticity; NF-kappa B; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a group of severe, tissue-specific diseases of childhood with unknown pathogenesis. Brain-specific MDS manifests as devastating spongiotic encephalopathy with no curative therapy. Here, we report cell type-specific stress responses and effects of rapamycin treatment and ketogenic diet (KD) in mice with spongiotic encephalopathy mimicking human MDS, as these interventions were reported to improve some mitochondrial disease signs or symptoms. These mice with astrocyte-specific knockout of

Topics: Animals; Astrocytes; Brain Diseases; Diet, Ketogenic; Disease Models, Animal; DNA Helicases; DNA Replication; DNA, Mitochondrial; Female; Ketosis; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Neurons; Sirolimus; Stress, Physiological

The hypothalamus regulates metabolism and feeding behavior by perceiving the levels of peripheral insulin. However, little is known about the hypothalamic changes after aberrant metabolism. In this study, we investigated the changes of insulin and autophagy relevant signals of hypothalamus under diabetes mellitus.. C57B/L mice were injected with low-dose streptozotocin (STZ) and fed with high-fat diet to induce type 2 diabetes mellitus. In vitro, PC12 cells were treated with oleic acid to mimic lipotoxicity.. Results showed that the cholesterol level in the hypothalamus of the diabetic mice was higher than that of the normal mice. The expression of insulin receptors and insulin receptor substrate-1 were downregulated and the number of Fluoro-Jade C positive cells significantly increased in the hypothalamic arcuate nucleus of the diabetic mice. Furthermore, Upregulation of mammalian target of rapamycin (mTOR) and downregulation of LC 3II were obvious in the hypothalamus of the diabetic mice. In vitro, results showed that high-lipid caused PC12 cell damage and upregulated LC3 II expression. Pretreatment of cells with 3-methyladenine evidently downregulated LC3 II expression and aggravated PC12 cell death under high lipid conditions. By contrast, pretreatment of cells with rapamycin upregulated LC3 II expression and ameliorated PC12 cell death caused by lipotoxicity.. These results demonstrate that autophagy activation confers protection to neurons under aberrant metabolism and that autophagy dysfunction in the hypothalamus occurs in the chronic metabolic disorder such as T2DM.

Topics: Adenine; Animals; Arcuate Nucleus of Hypothalamus; Autophagy; Blotting, Western; Brain Diseases; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Down-Regulation; Glucose Tolerance Test; Hypothalamus; Immunosuppressive Agents; In Vitro Techniques; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Oleic Acid; PC12 Cells; Rats; Receptor, Insulin; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation; Ventromedial Hypothalamic Nucleus

Topics: Action Potentials; Animals; Apoptosis; Autophagy; Brain Diseases; Disease Models, Animal; Epilepsy; Neuroprotective Agents; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Topics: Adult; Brain Diseases; Female; Graft vs Host Disease; Hodgkin Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Peripheral Blood Stem Cell Transplantation; Sirolimus; Syndrome

Neurotoxicity is a common adverse effect of cyclosporine (CsA) in transplant recipients. Although most patients develop mild toxic manifestations, leukoencephalopathy with seizures, visual complications, psychiatric symptoms and motor and speech disorders may occur. Whether everolimus exacerbates the neurotoxicity of CsA is not known. We describe a patient who developed severe neurologic complications, consistent with CsA-induced neurotoxicity, developing 7.5 years after cardiac transplantation, 3 months after everolimus was added to the immunosuppressive regimen.

Topics: Brain Diseases; Cardiomyopathy, Dilated; Cyclosporine; Everolimus; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Sirolimus; Ventricular Dysfunction, Right

Posterior Leukoencephalopathy Syndrome (PLES) is a rare but serious neurological condition with many aetiologies. In the era of organ transplantation there have been sporadic reports of calcineurin-inhibitor associated PLES. We describe a case, with subsequent uneventful retransplantation using sirolimus.

Topics: Brain Diseases; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Male; Reoperation; Sirolimus; Syndrome; Tacrolimus

Topics: Brain Diseases; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus