Type-3 diabetes mellitus (T3D) is a pathological condition that possesses the characteristics of both Diabetes and Alzheimer's disease, considered as brain diabetes. Treatment of T3D is still a challenging task for clinical practitioners. In this regard, this study was carried out to explore the effect of Insulin and Rivastigmine in the experimental rats. T3D was induced by administering streptozotocin (STZ; 35 mg/kg, i.p., single dose) followed by daily administration of aluminum chloride (AlCl 3 ) (12.5 mg/kg, i.p. × 28 days). The Insulin (1 IU s.c. daily × 28 days) and Rivastigmine (1 mg/kg, i.p. × 28 days) treatment was given 30 minutes prior to administration of AlCl 3 . After 28 days of treatment, the rats were subjected to the estimation of various behavioral parameters using elevated plus maze (EPM) and Morris water maze (MWM) test and biochemical parameters including Insulin, glucose, malondialdehyde (MDA), nitrite, and amyloid beta (Aβ) levels. The results obtained revealed that the Insulin administration increased the square crossings in the open field, and reduced the transfer latency of T3D rats in the closed arm of EPM at day 2 and the frequency of platform crossing in the MWM test in T3D rats. The administration of Insulin and Rivastigmine reduced the blood glucose level and Aβ levels in the brain of T3D rats. Furthermore, Rivastigmine treatment also reduced the brain Insulin level of T3D rats. These studies indicate toward the beneficial effects of Insulin and Rivastigmine that open newer opportunities in the management protocol of T3D.
The present study is designed to develop Type-3 diabetes mellitus characterized by insulin resistance, mainly at the brain level. The experimental rats in group-1: received vehicle (5 ml/kg, i.p.) for 28 days, group-2-4: received aluminium chloride (AlCl3) (12.5, 25, and 50 mg/kg, i.p.) daily for 28 days, group-5: received single dose of STZ (45 mg/kg, i.p.), and group-6-8: received STZ and AlCl3 (12.5, 25, and 50 mg/kg, i.p. daily for 28 days) from the third day of STZ administration. The behavioral analysis was initiated on the 29th day, estimating locomotor activity using an open field test, learning and memory-related functions using elevated plus maze (EPM) and morris water maze (MWM) tests. Afterwards, the rats were sacrificed, and brain and blood were collected for whole-brain neurochemical and plasma biochemical assays, including glucose, insulin, nitrite, MDA and amyloid-beta levels. The brain tissues were sectioned, followed by H&E and congo red staining for histopathological examination. The results obtained demonstrated that the STZ pretreatment and AlCl3 (12.5 mg/kg) treatment significantly impaired the cognition in EPM and MWM. Also, the STZ pretreatment and AlCl3 (12.5 mg/kg) treatment significantly increased the brain glucose levels, brain insulin levels, lipid peroxidation and amyloid levels, suggesting the development of hyperinsulinemia, insulin resistance and amyloid pathology. Further, STZ pretreatment and AlCl3 (12.5 mg/kg) treated rats produced the marked degenerated neurons, neuronal loss, and the marked deposition of amyloid fibrils suggesting the development of neurodegenerative changes. In conclusion, the present findings suggested that administering low doses of AlCl3 to the STZ pretreated experimental rats results in the development of marked hyperinsulinemia, insulin resistance, cognitive impairment, amyloid-beta deposition, and neuronal degeneration, reflects the features of Type-3 diabetes mellitus (T3DM).
Autophagy is a normal physiological process characterized by the degradation of complex cellular contents into a simpler one and reutilized them in biosynthetic pathways. Lysosomes are the cell organelle that participates in the process of autophagy. The brain is the most vulnerable organ in most lysosome disorders because neurons are inefficient in removing impaired organelles and waste materials. In the brain, autophagy suppresses the accumulation of ubiquitinated proteins that results in further damage to the neurons responsible for neurodegeneration. Autophagy mediates protective effects in age-related diseases. In the chapter, the authors describe the process of autophagy, the mechanism involved, and the implication of the autophagic pathways in the various neurodegenerative disorders.
Mitophagy is a selective autophagy process in which damaged or surplus mitochondria are removed to sustain normal homeostasis. The efficient removal of damaged or stressed mitochondria is crucial for cellular health. Recent literature emphasizes the role of PINK1-Parkin pathways in the pathogenesis process of various neurodegenerative disorders. Further, mitophagy has shown potential therapeutic activity in treating neurodegenerative diseases. Thus, mitophagy might be important in the field of pharmacotherapeutics. In the present chapter, the authors explain mitophagy, mitophagy signaling pathways, as well as mechanisms and roles of mitophagy in various neurodegenerative disorders.
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