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Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4.

ABSTRACT: Background:Neuroprotective mechanisms triggered by peroxisome proliferator-activated receptor-gamma agonist: pioglitazone (PIO) and glucagon-like peptide 1 analog: exendin-4 (Ex-4) in neurological diseases were reported, but whether mitochondrial biogenesis is involved or not in their neuro-protective mechanisms in type 1 Diabetes Mellitus (T1DM); has not been studied before. To bridge this gap, we investigated the effect of PIO and Ex-4 on brain mitochondrial biogenesis in streptozotocin- induced diabetes in rats. Methods:Seven weeks after induction of diabetes in rats, serum fasting glucose and insulin were measured in studied groups. The brain was removed for histological analysis and assessment of: mitochondrial complexes I and II, ATP, H2O2, brain derived neurotrophic factor (BDNF), cytochrome c and hemeoxygenase (HO)-1 activity, and relative gene expression of the nuclear factor; Nrf2 and the apoptotic markers: bax & bcl2 and mitochondrial biogenesis markers; peroxisome proliferator-activated receptor ? coactivator (PGC) 1-? and sirtuin 1 (SIRT-1) and AMP-activated protein kinase (AMPK) and c-Jun-N-terminal kinase (JNK) proteins. Results:Brain in untreated rats showed neurodegeneration area and significantly rising H2O2 and JNK, up-regulation of bax, down-regulation of bcl2. These changes were paralleled with significant reduction in Nrf2, HO-1, BDNF, complex I, II and ATP and SIRT-1/ PGC1-? expression. PIO and Ex-4 significantly improved the reported changes. Combined modality showed better improvement relative to each drug alone. Conclusion:PIO and Ex-4 may have neuroprotective effects in T1DM, via targeting altered mitochondrial biogenesis probably due to modulation of brain SIRT-1 signaling, improvement of oxidative stress and equilibrating the balance between pro-apoptotic and anti-apoptotic mediators.

SUBMITTER: Mostafa Tork O

PROVIDER: S-EPMC7103073 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4.

Mostafa Tork Ola O Ahmed Rashed Laila L Bakr Sadek Nermeen N Abdel-Tawab Marwa Sayed MS

Reports of biochemistry & molecular biology 20191001 3

<h4>Background</h4>Neuroprotective mechanisms triggered by peroxisome proliferator-activated receptor-gamma agonist: pioglitazone (PIO) and glucagon-like peptide 1 analog: exendin-4 (Ex-4) in neurological diseases were reported, but whether mitochondrial biogenesis is involved or not in their neuro-protective mechanisms in type 1 Diabetes Mellitus (T1DM); has not been studied before. To bridge this gap, we investigated the effect of PIO and Ex-4 on brain mitochondrial biogenesis in streptozotoci ...[more]

PMID: 32274400

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Project description:The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor ? coactivator 1-? (PGC-1?) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1?. To determine how IL-1? affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1?. IL-1? induced mitochondrial activity within 30?min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1?-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) ?. A PPAR? antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.

Project description:Background and purposeReperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia.MethodsMale Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting.ResultsEvidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1α returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex.ConclusionsThese results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.

Project description:OBJECTIVES:Diabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM. METHODS:Closed transverse fractures were created in the femurs of 116 rats, with half assigned to the DM group and half assigned to the control group. Rats with DM were induced by a single intraperitoneal injection of streptozotocin. At post-fracture days five, seven, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture days five and 11. For further analysis, real-time polymerase chain reaction (PCR) analysis was performed at each timepoint. RESULTS:Microarray analysis showed that there were 14 miRNAs at day five and 17 miRNAs at day 11, with a greater than twofold change in the DM group compared with the control group. Among these types of miRNA, five were selected based on a comparative and extended literature review. Real-time PCR analysis revealed that five types of miRNA (miR-140-3p, miR-140-5p, miR-181a-1-3p, miR-210-3p, and miR-222-3p) were differentially expressed with changing patterns of expression during fracture healing in diabetic rats compared with controls. CONCLUSIONS:Our findings provide information to further understand the pathology of impaired fracture healing in a diabetic rat model. These results may allow the potential development of molecular therapy using miRNA for the treatment of impaired fracture healing in patients with DM.Cite this article: S. Takahara, S. Y. Lee, T. Iwakura, K. Oe, T. Fukui, E. Okumachi, T. Waki, M. Arakura, Y. Sakai, K. Nishida, R. Kuroda, T. Niikura. Altered expression of microRNA during fracture healing in diabetic rats. Bone Joint Res 2018;7:139-147. DOI: 10.1302/2046-3758.72.BJR-2017-0082.R1.

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Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4.

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Targeting Altered Mitochondrial Biogenesis in the Brain of Diabetic Rats: Potential Effect of Pioglitazone and Exendin-4.

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