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Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase ( Dio2 ) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase ( Dio3 ) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin , genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro . Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes ( VEGF, Enolase, HIF2α, c-Jun ) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless , important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). The glucagon-like peptide-1 analog liraglutide, a novel long-lasting incretin hormone, has been used to treat type 2 diabetes mellitus. In addition, liraglutide has been shown to be neurotrophic and neuroprotective. Here, we investigated the effects of liraglutide on amyloid β protein (Aβ)-induced AD in mice and explored its mechanism of action. The results showed that subcutaneous administration of liraglutide (25nmol/day), once daily for 8 weeks, prevented memory impairments in the Y Maze and Morris Water Maze following Aβ 1–42 intracerebroventricular injection, and alleviated the ultra-structural changes of pyramidal neurons and chemical synapses in the hippocampal CA1 region. Furthermore, liraglutide reduced Aβ 1–42 -induced tau phosphorylation via the protein kinase B and glycogen synthase kinase-3β pathways. Thus liraglutide may alleviate cognitive impairment in AD by at least decreasing the phosphorylation of tau. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the relationship between astrocytes and recurrent non-severe hypoglycemia (RH)2 -associated cognitive decline in diabetes. RH induced cognitive impairment and neuronal cell death in the cerebral cortex of diabetic mice, accompanied by excessive activation of astrocytes. Levels of the neurotrophins BDNF and GDNF, together with BDNF and GDNF- related signaling, were downregulated by RH. In vitro , recurrent low glucose (RLG)3 impaired cell viability and induced apoptosis of high-glucose cultured astrocytes. Accumulating mitochondrial ROS and dysregulated mitochondrial functions, including abnormal morphology, decreased membrane potential, downregulated ATP levels, and disrupted bioenergetic status, were observed in these cells. SS-31 mediated protection of mitochondrial functions reversed RLG-induced cell viability defects and neurotrophin production. These findings demonstrate that RH induced astrocyte overactivation and mitochondrial dysfunction, leading to astrocyte-derived neurotrophin disturbance, which might contribute to diabetic cognitive decline. Targeting astrocyte mitochondria might represent a neuroprotective therapy for hypoglycemia-associated neurodegeneration in diabetes. • RH induced neurodegeneration and excessive activation of the cortical astrocytes. • RH disrupted neurotrophin level and the related signaling in the cerebral cortex of diabetic mice. • RLG induced mitochondrial ROS accumulation in astrocytes in high glucose culture. • RLG impaired mitochondrial function of astrocytes in high glucose culture. • RLG-induced mitochondrial dysfunction reduced astrocytic neurotrophin synthesis and secretion. [ABSTRACT FROM AUTHOR]

• Exenatide improves spatial memory and learning ability in 5xFAD mice. • Exenatide reduces hippocampal A 1-42 deposits and synaptic degradation in 5xFAD mice. • Exenatide improves hippocampal mitochondrial morphology and dynamics in 5xFAD mice. • Exenatide reduces oxidative stress in the hippocampus of 5xFAD mice. • Exenatide is a promising agent for AD therapy via mitochondrial protection. The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on β-amyloid plaque (Aβ)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 μg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aβ 1-42 deposition and synapse damage in the hippocampus was significantly alleviated. Furthermore, exenatide treatment can improve mitochondrial morphology, relieve oxidative damage, correct mitochondrial energy crisis, and normalize mitochondrial dynamics. These findings suggest that exenatide, which has already been applied in clinical medicine, may be a promising agent for AD therapy via mitochondrial protection. [ABSTRACT FROM AUTHOR]