RESUMEN
Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-ß deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3ß, MDA, TNF-α, and IL-1ß in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-ß burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Donepezilo/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicología , Donepezilo/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Resistencia a la Insulina , Discapacidades para el Aprendizaje/tratamiento farmacológico , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Prueba del Laberinto Acuático de Morris , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
OBJECT: Glutamate is important in the pathogenesis of brain damage after cerebral ischemia and traumatic brain injury. Notably, brain extracellular and cerebrospinal fluid as well as blood glutamate concentrations increase after experimental and clinical trauma. While neurons are one potential source of glutamate, platelets also release glutamate as part of their recruitment and might mediate neuronal damage. This study investigates the hypothesis that platelet microthrombi release glutamate that mediates excitotoxic brain injury and neuron dysfunction after subarachnoid hemorrhage (SAH). METHODS: The authors used two models, primary neuronal cultures exposed to activated platelets, as well as a whole-animal SAH preparation. Propidium iodide was used to evaluate neuronal viability, and surface glutamate receptor staining was used to evaluate the phenotype of platelet-exposed neurons. RESULTS: The authors demonstrate that thrombin-activated platelet-rich plasma releases glutamate, at concentrations that can exceed 300 µM. When applied to neuronal cultures, this activated plasma is neurotoxic, and the toxicity is attenuated in part by glutamate receptor antagonists. The authors also demonstrate that exposure to thrombin-activated platelets induces marked downregulation of the surface glutamate receptor glutamate receptor 2, a marker of excitotoxicity exposure and a possible mechanism of neuronal dysfunction. Linear regression demonstrated that 7 days after SAH in rats there was a strong correlation between proximity to microthrombi and reduction of surface glutamate receptors. CONCLUSIONS: The authors conclude that platelet-mediated microthrombosis contributes to neuronal glutamate receptor dysfunction and might mediate brain injury after SAH.