RESUMEN
Ischemic stroke often co-occurs with Alzheimer's disease (AD) leading to a worsened clinical outcome. Neuroinflammation is a critical process implicated in AD and ischemic pathology, associated with cognitive decline. We sought to investigate the combined effects of ischemic stroke induced by endothelin-1 injection in two AD rat models, using motor function, memory and microglial inflammation in the basal forebrain and striatum as readouts. In addition, we sought to determine the effectiveness of the antioxidant biologic CAT-SKL in one of the models. The early AD model employed the bilateral intracerebroventricular injections of the toxic ß-amyloid peptide Aß25-35, the prodromal AD model used the transgenic Fischer 344 rat overexpressing a pathological mutant human amyloid precursor protein. Motor function was assessed using a cylinder, modified sticky tape and beam-walk tasks; learning and memory were tested in the Morris water maze. Microglial activation was examined using immunohistochemistry. Aß25-35 toxicity and stroke combination greatly increased microglial inflammation in the basal forebrain. Prodromal AD-pathology coupled with ischemia in the transgenic rat resulted in a greater microgliosis in the striatum. Combined transgenic rats showed balance alterations, comorbid Aß25-35 rats showed a transient sensorimotor deficit, and both demonstrated spatial reference memory deficit. CAT-SKL treatment ameliorated memory impairment and basal forebrain microgliosis in Aß25-35 rats with stroke. Our results suggest that neuroinflammation could be one of the early processes underlying the interaction of AD with stroke and contributing to the cognitive impairment, and that therapies such as antioxidant CAT-SKL could be a potential therapeutic strategy.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/metabolismo , Microglía/metabolismo , Ratas , Ratas Transgénicas , Accidente Cerebrovascular/patologíaRESUMEN
BACKGROUND: Decreased oxygenation of muscle may be accentuated during exercise at high altitude. Monitoring the oxygen saturation of muscle (SmO2) during hand grip exercise using near infrared spectroscopy during acute exposure to hypoxia could provide a model for a test of muscle performance without the competing cardiovascular stresses that occur during a cycle ergometer or treadmill test. The purpose of this study was to examine and compare acute exposure to normobaric hypoxia versus normoxia on deoxygenation and recruitment of the flexor digitorum superficialis (FDS) during submaximal intermittent handgrip exercise (HGE) in healthy adults. METHODS: Twenty subjects (11 M/9 F) performed HGE at 50% of maximum voluntary contraction, with a duty cycle of 2 s:1 s until task failure on two occasions one week apart, randomly assigned to normobaric hypoxia (FiO2 = 12%) or normoxia (FiO2 = 21%). Near-infrared spectroscopy monitored SmO2, oxygenated (O2Hb), deoxygenated (HHb), and total hemoglobin (tHb) over the FDS. Surface electromyography derived root mean square and mean power frequency of the FDS. RESULTS: Hypoxic compared to normoxic HGE induced a lower FDS SmO2 (63.8 ± 2.2 vs. 69.0 ± 1.5, p = 0.001) and both protocols decreased FDS SmO2 from baseline to task failure. FDS mean power frequency was lower during hypoxic compared to normoxic HGE (64.0 ± 1.4 vs. 68.2 ± 2.0 Hz, p = 0.04) and both decreased mean power frequency from the first contractions to task failure (p = 0.000). Under both hypoxia and normoxia, HHb, tHb and root mean square increased from baseline to task failure whereas O2Hb decreased and then increased during HGE. Arterial oxygen saturation via pulse oximetry (SpO2) was lower during hypoxia compared to normoxia conditions (p = 0.000) and heart rate and diastolic blood pressure only demonstrated small increases. Task durations and the tension-time index of HGE did not differ between normoxic and hypoxic trials. CONCLUSION: Hypoxic compared to normoxic HGE decreased SmO2 and induced lower mean power frequency in the FDS, during repetitive hand grip exercise however did not result in differences in task durations or tension-time indices. The fiber type composition of FDS, and high duty cycle and intensity may have contributed greater dependence on anaerobiosis.
RESUMEN
Accumulation of beta-amyloid (Aß) in the brain has been implicated as a major contributor to the cellular pathology and cognitive impairment observed in Alzheimer's disease. Beta-amyloid may exert its toxic effects by increasing reactive oxygen species and neuroinflammation in the brain. This study set out to investigate whether a genetically engineered derivative of the peroxisomal antioxidant enzyme catalase (CAT-SKL), is able to reduce the toxicity induced by intracerebroventricular injection of Aß25-35 in the mature rat brain. Histopathological and immunohistochemical analyses were used to evaluate neuroinflammation, and neuronal loss. Spatial learning and reference memory was assessed using the Morris water maze. CAT-SKL treatment was able to reduce the pathology induced by Aß25-35 toxicity by significantly decreasing microglia activation in the basal forebrain and thalamus, and reducing cholinergic loss in the basal forebrain. Aß25-35 animals showed deficits in long-term reference memory in the Morris water maze, while Aß25-35 animals treated with CAT-SKL did not demonstrate long-term memory impairments. This preclinical data provides support for the use of CAT-SKL in reducing neuroinflammation and long-term reference memory deficits induced by Aß25-35.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Antioxidantes/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/toxicidad , Animales , Encéfalo/enzimología , Catalasa/análisis , Muerte Celular , Evaluación Preclínica de Medicamentos , Discapacidades para el Aprendizaje/tratamiento farmacológico , Discapacidades para el Aprendizaje/prevención & control , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Microglía/efectos de los fármacos , Microglía/fisiología , Proteínas del Tejido Nervioso/análisis , Neuronas/efectos de los fármacos , Neuronas/patología , Prosencéfalo/química , Prosencéfalo/efectos de los fármacos , Prosencéfalo/patología , Distribución Aleatoria , Ratas , Ratas Wistar , Aprendizaje Espacial/efectos de los fármacos , Tálamo/química , Tálamo/efectos de los fármacos , Tálamo/patologíaRESUMEN
Alzheimer's disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke. For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient.