h-89 and Nervous-System-Diseases

Mitochondrial dysfunction has been associated with the pathogenesis of a variety of neurodegenerative diseases. Sitagliptin is a dipeptidyl-peptidase-4 (DPP-4) inhibitor that has been approved for the treatment of type 2 diabetes (T2DM). In the current study, we report that sitagliptin increased the expression of PGC-1α, NRF1, and TFAM in human SH-SY5Y neuronal cells. Notably, our data indicate that sitagliptin promoted mitochondrial biogenesis by increasing the amount of mtDNA, the levels of mitochondria-related genes such as TOMM20, TOMM40, TIMM9, NDUFS3, ATP5C1, and the expression of oxidative phosphorylation subunits complex I and complex IV. Additionally, we found that sitagliptin induced a "gain of mitochondrial function" in SH-SY5Y cells by increasing the mitochondrial respiratory rate and adenosine triphosphate (ATP) production. Significantly, our results demonstrate that sitagliptin activated the transcriptional factor CREB by inducing its phosphorylation at Ser133. Inhibition of CREB using its specific inhibitor H89 abolished the effects of sitagliptin on the expression of PGC-1α, NRF1, and TFAM, as well as an increase in mtDNA amount and ATP production. These findings suggest that sitagliptin could become a potential agent for the treatment of neurological disorders.

Topics: Adenosine Triphosphate; Animals; Cell Line; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; DNA-Binding Proteins; Humans; Isoquinolines; Mitochondria; Mitochondrial Proteins; Nervous System Diseases; Nuclear Respiratory Factor 1; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sitagliptin Phosphate; Sulfonamides; Transcription Factors

Decreased 3'-5'-cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and increased N-methyl-d-aspartate (NMDA) related apoptosis were observed in traumatic brain injury (TBI). It is of interest to examine the effect of magnesium lithospermate B (MLB) on cAMP/PKA pathway and NMDAR in TBI.. A rodent weight-drop TBI model was used. Administration of MLB was initiated 1 week before (precondition) and 24 hours later (reversal). Cortical homogenates were harvested to measure cAMP (enzyme-linked immunosorbent assay), soluble guanylyl cyclases, PKA and NMDA receptor-2β (Western blot). In addition, cAMP kinase antagonist and H-89 dihydrochloride hydrate were used to test MLB's effect on the cytoplasm cAMP/PKA pathway after TBI.. Morphologically, vacuolated neuron and activated microglia were observed in the TBI groups but absent in the MLB preconditioning and healthy controls. Induced cAMP, soluble guanylyl cyclase α1, and PKA were observed in the MLB groups, when compared with the TBI group (P < 0.01) Administration of H-89 dihydrochloride hydrate reversed the effect of MLB on cortical PKA and NMDA-2β expression after TBI.. This study showed that MLB exerted an antioxidant effect on the enhancement of cytoplasm cAMP and PKA. This compound also decreased NMDA-2β levels, which may correspond to its neuroprotective effects. This finding lends credence to the presumption that MLB modulates the NMDA-2β neurotoxicity through a cAMP-dependent mechanism in the pathogenesis of TBI.

Topics: Animals; Behavior, Animal; Brain Edema; Brain Injuries; Cerebral Cortex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Drugs, Chinese Herbal; Enzyme Inhibitors; Free Radical Scavengers; Guanylate Cyclase; Isoquinolines; Male; Nervous System Diseases; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Soluble Guanylyl Cyclase; Sulfonamides