Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins

Eslami Gharaati, Maryam; Nahavandi, Arezo; Baluchnejad Mojarad, Torandokht; Roghani, Mehrdad

doi:10.32598/bcn.11.6.1657.1

Volume 11, Issue 6 (November & December 2020) BCN 2020, 11(6): 781-794 | Back to browse issues page

‎ 10.32598/bcn.11.6.1657.1

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Eslami Gharaati M, Nahavandi A, Baluchnejad Mojarad T, Roghani M. Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins. BCN 2020; 11 (6) :781-794
URL: http://bcn.iums.ac.ir/article-1-1396-en.html

Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins

Maryam Eslami Gharaati¹

, Arezo Nahavandi ^*

¹, Torandokht Baluchnejad Mojarad¹

, Mehrdad Roghani²

1- Department of Physiology, School of Medicine, Iran University of Medical Science, Tehran, Iran.
2- Departmentof Physiology, Neurophysiology Research Center, Shahed University, Tehran, Iran.

Abstract:

Introduction: Diabetic encephalopathy is described as any cognitive and memory impairments associated with hippocampal degenerative changes, including the neurodegenerative process and decreased number of living cells. Mitochondrial diabetes (MD) appears following activation of mutant mitochondrial DNA and is a combination of diabetes and cognitive deficit. In this research, we showed the correlation of diabetic encephalopathy, dysfunctional mitochondria, and changes in the expression of axonal transport proteins (KIF5b, Dynein).
Methods: Twenty-four male Wistar rats were divided into three groups: (n=8 in each group):1. Control + saline; 2. Diabetic, and 3. Diabetic + insulin. Before starting the experiments, the animals with blood sugar lower than 150 mg/dL entered the study. Diabetes induction was carried out by Intraperitoneal (IP) Streptozotocin (STZ) administration. Fasting Blood Sugar (FBS) and body weight was checked after the first week and at the end of the eighth week. Then, behavioral studies (elevated plus maze, Y-maze, and passive avoidance learning) were performed. After behavioral studies, blood samples were taken to measure serum insulin level and HgbA1c. Next, fresh hippocampal tissue was collected. Gene expression of motor proteins was assessed by real-time PCR and mitochondrial membrane potential by rhodamine123.
Results: Our results showed the impairment of HgbA1c, serum insulin, FBS, and weight in the diabetic group (P<0.05). Behavioral tests revealed different degrees of impairment in diabetic rats (P<0.05). KIF5b mRNA expression increased in the hippocampus (P<0.05) with no change in dynein gene expression. These changes were associated with abnormal mitochondrial membrane potential (P<0.05).
Conclusion: KIF5b mRNA up-regulation in hippocampal neurons of STZ-diabetic rats is a factor that can be involved in abnormal axonal transport and decreased MMP, leading to impairment of mitochondrial function. These manifestations showed mitochondrial dysfunction in diabetes and resulted in abnormal behavioral tests and diabetic encephalopathy.

Keywords: Diabetes mellitus type 1, Mitochondrial encephalopathy, Axonal transport, Mitochondria, KIF5b protein, Dynein

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● Short-term memory impairment and retrieval deficit in combination with anxiety-like behavior were observed 8 weeks after the onset of diabetes.
● Biochemical changes of impaired glycosylated hemoglobin (HgbA1c) and serum insulin level were observed in diabetic rats.
● Cellular changes in decreased mitochondrial membrane potential in the hippocampus were observed in diabetic rats.
● Molecular changes of increased kinesin (KIF5b) gene expression levels in the hippocampus were observed in diabetic rats.
● After 8 weeks of insulin injection, KIF5b gene expression levels were reversed.

Plain Language Summary
Diabetes Mellitus (DM) is strongly associated with degenerative and functional disorders in the Central Nervous System (CNS). One of the most chronic complications of DM in CNS is “diabetic encephalopathy.” According to the definition, any cognitive impairment affected by diabetes is called diabetic encephalopathy and or type 3 diabetes mellitus (T3DM). Several studies show mitochondrial dysfunction in different regions of the brain. Also, mitochondrial movement and transport are disrupted in diabetic condition. The mechanisms underlying those impairments are still unknown. In this work, we evaluated the effect of diabetic encephalopathy on mitochondrial function and transport by studying the proteins (KIF5b & dynein) that are involved in axonal transport of mitochondria in male rats. After 8 weeks of induction of diabetes (by a single dose of STZ), the animals were monitored by behavioral test (elevated plus maze, Y-maze, and passive avoidance learning), biochemical parameters (HgbA1c and insulin), and mitochondrial function and transport using rhodamine 123 staining and real-time PCR. We showed that diabetic encephalopathy resulted in cognitive decline and mitochondrial dysfunction by decreased Mitochondrial Membrane Potential (MMP) and kinesin gene overexpression. We suggested that abnormal translocation of mitochondria and its malfunction induced by kinesin gene overexpression possibly resulted in cognitive and memory impairment in diabetic encephalopathy.

Type of Study: Original | Subject: Cellular and molecular Neuroscience
Received: 2018/12/30 | Accepted: 2019/05/13 | Published: 2020/11/1

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