Cinepazide Maleate Improves Cognitive Function and Protects Hippocampal Neurons in Diabetic Rats with Chronic Cerebral Hypoperfusion

Abstract

To determine the combined effect of type 2 diabetes (T2D) and chronic cerebral hypoperfusion (CCH) on learning and spatial memory, we developed a rat model of CCH by permanent occlusion of bilateral common carotid arteries (2-vessel occlusion (2VO)) in high-fat diet (HFD)-fed rats injected with low-dose streptozotocin (STZ). Furthermore, we examined the effect of cinepazide maleate (CM) on cognitive deficits and brain damage in this rat model. Rats were maintained on HFD for 6 weeks and then injected with 35 mg/kg STZ to induce T2D. Sham or 2VO surgery was performed in non-diabetic or diabetic (DM) rats to obtain four groups: blank, DM, CCH, and DM-CCH groups. Cognitive function was tested by the Morris water maze (MWM) test. To determine the effects of the vasodilator cinepazide maleate (CM) on cognitive deficits and brain damage, DM-CCH rats were administered with 10 mg/kg CM or saline daily for 14 d. Neuronal damage in DM-CCH rats was associated with increased expression of glial fibrillary acidic protein (GFAP) and β-secretase 1 (BACE1), but decreased expression of choline acetyltransferase (ChAT). Moreover, the levels of all these proteins were significantly alleviated by CM treatment. These results suggest that T2D exacerbated CCH-induced brain damage and cognitive impairment, and CM ameliorated these effects.Key words diabetes; chronic cerebral hypoperfusion; cognitive impairment; cinepazide maleate Chronic cerebral hypoperfusion (CCH) is thought to be an important factor contributing to cognitive decline, both in aging and in age-related neurological disorders.1-3) The severity of memory dysfunction and the decline in cerebral blood flow are strongly correlated in disorders, such as Alzheimer's disease (AD), vascular dementia, and stroke.4,5) Diabetes is one of the fastest growing epidemics worldwide and diabetic patients are at a high risk for development of cognitive impairment or dementia. 6) Moreover, diabetes is often associated with CCH, and can further aggravate neurodegeneration.Permanent bilateral occlusion of both common carotid arteries (or 2-vessel occlusion, 2VO) is a widely used rodent model of CCH. As the model mimics several features of human AD and vascular dementia, it is used to investigate the consequences of hypoperfusion on cerebral blood flow, cognitive ability, and histopathology in these neurological disorders.2,7) Progressive cognitive impairment has been reported after 2VO in rats, 2,[8][9][10][11] and behavioral changes resulting from cognitive impairment are associated with delayed loss of neurons in the hippocampal CA1 region, a feature commonly observed in human aging and dementia.2) CA1 cell loss is characterized by gliosis, cholinergic dysfunction, 12) and activation of β-secretase 1 (BACE1).13) Consistent memory impairment after 2VO in rats occurs in the chronic phase of the ischemic event, i.e., up to 3 months after surgery, and not within 7 d, as assessed by water maze and object recognition tasks. 14)Cinepazide maleate (CM) is a calcium-channel blocker with vasodilato...

<i>N</i>-Linoleyltyrosine Protects against Transient Cerebral Ischemia in Gerbil <i>via</i> CB2 Receptor Involvement in PI3K/Akt Signaling Pathway

“…The pronounced deletion of the neurons in the hippocampus is related to aggravated damages of animal behavior disorder, such as the performance in spatial learning and memory. 21) The present studies confirmed that more than 80% of the neurons in the hippocampus were damaged after a 5-min occlude in HE staining and Nissl staining. It was also noticeable that NITyr significantly reduce neuronal damage and provided adequate protection for the hippocampus, including neuronal loss, smaller size, irregular shape, deepened cytoplasm, and atrophic nuclei.…”

“…Thus, we selected 10 mg/kg NITyr for subsequent experiments. Nimodipine has been widely used in the treatment of brain injury, 20) there it is used as a positive drug in the experiment.…”

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

“…As a major risk factor for T2DM, obesity is closely associated with insulin resistance, which can be induced by HFD [23,24]. Moreover, a low dose of STZ has been widely used to induce T2DM in rodents by targeting beta cells [17,25]. Accordingly, rats were fed a HFD to produce insulin resistance, followed by a low-dose STZ injection to induce beta cell dysfunction and subsequently hyperglycemia [26].…”

“…After 1 week of adaptive feeding, the rats were randomly divided into four groups: sham non-diabetic rats (low-fat control diet, LFD + sham) (Sham), sham T2DM rats (high-fat diet + streptozotocin, HFD + STZ + sham) (DM), hypoperfused group (LFD + BCCAO) (CCH), and hypoperfused T2DM rats (HFD+STZ+BCCAO) (DM CCH) (each group n = 9). The T2DM rat model was developed according to the method in our previous study with slight modifications [17]. LFD consisted of 10% fat, 70% carbohydrate, and 20% protein, while HFD consisted of 60% fat, 20% carbohydrate, and 20% protein.…”

Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen‑activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin

“…However, the extent of islet β cell damage is dose-dependent ( 9 ). Following investigation of STZ dosage, 35 mg/kg has been identified as the optimal dosage of STZ to induce DM ( 10 , 11 ). Furthermore, increased doses of STZ have been associated with increased mortality in animals ( 12 ).…”