A Novel Role for the Calcium Sensing Receptor in Rat Diabetic Encephalopathy

Abstract

Background: Diabetic encephalopathy is a common complication of diabetes, and it may be involved in altering intracellular calcium concentrations ([Ca²⁺]_i) at its onset. The calcium sensing receptor (CaSR) is a G-protein coupled receptor, however, the functional involvement of CaSR in diabetic encephalopathy remains unclear. Methods: In this study, diabetic rats were modeled by STZ (50 mg/kg). At the end of 4, 8 and 12 weeks, the CaSR expression in hippocampus was analyzed by Western blot. In neonatal rat hippocampal neurons, the [Ca²⁺]_i was detected by laser scanning confocal microscopy, the production of reactive oxygen species (ROS) in mitochondria, the level of NO and the mitochondrial transmembrane potential were measured by MitoSOX, DAF-FM and JC-1, respectively. Results: Our results showed in hippocampal neurons treated with high glucose, CaSR regulated [Ca²⁺]_i through the PLC-IP3 pathway. CaSR expression was decreased and was involved in the changes in [Ca²⁺]_i. Mitochondrial membrane potential, NO release and expression of p-eNOS decreased, while the production of ROS in mitochondria increased. Conclusion: Down-regulation of CaSR expression was accompanied by neuronal injury, calcium disturbance, increased ROS production and decreased release of NO. Up-regulation of CaSR expression attenuated these changes through a positive compensatory protective mechanism to inhibit and delay diabetic encephalopathy in rats.

Inflammatory Macrophages Promotes Development of Diabetic Encephalopathy

“…Indeed, previous studies have demonstrated that diabetic encephalopathy is one of the main complications of severe diabetes, and is believed to result from hyperglycemic and inflammatory damages to brain vessels and causes dementia [9][10][11][12]. Moreover, diabetes may increase the risk of developing mild cognitive impairment, a condition in which people experience more cognitive and memory problems than are usually present in normal aging [9][10][11][12]. Mild cognitive impairment may lead to Alzheimer's disease and other types of dementia [9][10][11][12].…”

“…Many studies indicate that diabetic patients are at higher risk of developing dementia or Alzheimer's disease [1][2][3][4][5]. Indeed, diabetes can cause several complications, including diabetic encephalopathy, which is believed to result from hyperglycemic and inflammatory damages to brain vessels and causes dementia [9][10][11][12]. The link between diabetes and Alzheimer's may occur as a result of the complex ways.…”

“…The link between diabetes and Alzheimer's may occur as a result of the complex ways. For example, diabetes may increase the risk of developing mild cognitive impairment, a condition in which people experience more cognitive and memory problems than are usually present in normal aging [9][10][11][12]. Mild cognitive impairment may lead to Alzheimer's disease and other types of dementia [9][10][11][12].…”

“…Although hyperglycemia during diabetes is one major cause of encephalopathy, diabetes may also cause chronic inflammatory complications including peripheral neuropathy [9][10][11][12]. Since diabetes is one of the major risk factors for cerebrovascular disease, inflammatory process may take place in central nervous system (CNS).…”

“…Since diabetes is one of the major risk factors for cerebrovascular disease, inflammatory process may take place in central nervous system (CNS). Diabetic encephalopathy is characterized by impaired cognitive functions and neurochemical and structural abnormalities, and may involve direct neuronal damage caused by hyperglycemia [9][10][11][12]. However, brain inflammatory events during diabetes may be an important mechanism of brain damage and may be involved in diabetic encephalopathy.…”