ABSTRACT
Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.
Subject(s)
Cognitive Dysfunction/drug therapy , Dementia, Vascular/drug therapy , Neuroprotective Agents/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , Pyrrolidines/administration & dosage , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , Dementia, Vascular/metabolism , Dementia, Vascular/physiopathology , Disease Models, Animal , Male , Maze Learning/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.
Subject(s)
Animals , Male , Rats , Pyrrolidines/administration & dosage , Dementia, Vascular/drug therapy , Signal Transduction/physiology , Neuroprotective Agents/administration & dosage , Proto-Oncogene Proteins c-akt/metabolism , Cognitive Dysfunction/drug therapy , Autophagy/drug effects , Dementia, Vascular/physiopathology , Dementia, Vascular/metabolism , Rats, Sprague-Dawley , Apoptosis/drug effects , Maze Learning/drug effects , Disease Models, Animal , TOR Serine-Threonine Kinases/metabolism , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/metabolismABSTRACT
A sample of 50 isolates, including 25 each of the 3-acetyldeoxynivalenol and the 15-acetyldeoxynivalenol trichothecene genotype, from a contemporary collection of Fusarium graminearum associated with Fusarium head blight (FHB) of wheat in New York varied in sensitivity to tebuconazole (effective concentration leading to a 50% reduction of mycelial growth [EC50] of 0.28 to 8.09 mg/liter; µ = 1.12 mg/liter) and metconazole (0.05 to 0.86 mg/liter; µ = 0.33). Mean sensitivity did not differ between the trichothecene genotype groups. Isolate Gz448NY11 from Steuben County is the first tebuconazole-resistant field isolate of F. graminearum reported in the Americas and has the lowest sensitivity to tebuconazole (EC50 = 8.09 mg/liter) documented for this species. Suppression of FHB and deoxynivalenol (DON) following application of a commercial rate of tebuconazole was significantly diminished in plants inoculated with the tebuconazole-resistant isolate compared with those inoculated with a tebuconazole-sensitive isolate well documented for its aggressiveness and toxigenicity on wheat. There was no diminution of FHB and DON suppression with either isolate following application of metconazole. Significantly more individuals of the tebuconazole-resistant isolate were recovered from spikes inoculated with an equal mixture of the two isolates and sprayed with tebuconazole. Future studies are needed on the epidemiology and monitoring of triazole-resistant isolates to understand the risk that fungicide resistance poses to disease management and food security.