RESUMO

Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.

Assuntos

Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Canabidiol/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Fatores Etários , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Encéfalo/metabolismo , Canabidiol/farmacologia , Circulação Cerebrovascular/fisiologia , Doença Crônica , Comorbidade , Diabetes Mellitus Experimental/sangue , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento

RESUMO

Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH. After surgery, roflumilast (0.003 and 0.01 mg/kg) was administered intraperitoneally once per day for 29 days. Memory performance was assessed in the aversive radial maze (AvRM) 7, 14, and 21 days after CCH. The effects of roflumilast on hippocampal neurodegeneration and white matter injury were investigated using Nissl and Kluver-Barrera staining, respectively. Western blot and RT-qPCR were used to explore microglial polarization using M1 (Iba-1 and iNOS) and M2 (Arginase-1) markers. Chronic cerebral hypoperfusion caused persistent memory deficits, hippocampal neurodegeneration, and vacuolization and fiber disarrangement in white matter. Repeated roflumilast treatment restored CCH-induced cognitive impairments in aged rats but in the absence of the rescue of hippocampal neurons. Attenuation of white matter injury was detected in the optic tract in aged CCH rats that were treated with roflumilast. In vitro, roflumilast increased Arg-1 gene expression in myelin-laden primary microglia. The present data suggest that roflumilast might be useful for the treatment of cognitive sequelae associated with CCH.

Assuntos

Aminopiridinas/farmacologia , Benzamidas/farmacologia , Isquemia Encefálica/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Substância Branca/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Arginase/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Doença Crônica , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Trato Óptico/efeitos dos fármacos , Trato Óptico/metabolismo , Trato Óptico/patologia , Distribuição Aleatória , Ratos Wistar , Substância Branca/metabolismo , Substância Branca/patologia

RESUMO

Chronic cerebral hypoperfusion (CCH) may be involved in the etiology of aging-related dementias, and several risk factors contribute to their development and/or aggravation. We previously reported on the development of the 4-VO/ICA model of CCH, and the impact of hypertension on the cognitive and histological outcomes of CCH. Here, we advanced those studies by investigating how 4-VO/ICA alone or in combination with diabetes affects survival, body weight and cognitive performance in both young and middle-aged rats. Subsequently, middle-aged rats were examined for the impact of diabetes on CCH-induced neurodegeneration, white matter damage, and glial cells response. Diabetes alone reduced body weight and increased mortality rate slightly in young rats; these effects were striking, however, in the older animals. After CCH alone, neither body weight nor mortality rate changed significantly in both age groups. However, when CCH was combined with diabetes, mortality rate increased significantly in both aged groups. Young rats were cognitively asymptomatic to CCH, but they became 'mildly' impaired after CCH combined with diabetes. In middle-aged rats, CCH severely impaired memory, which was significantly worsened by diabetes. Moreover, diabetes aggravated neurodegeneration in the hippocampus and white matter injury in the corpus callosum and it promoted glial activation in the hippocampus and white matter of CCH middle-aged rats. These data suggest that diabetes interacts synergistically with age and reduces the capacity of the brain to adequately respond to CCH and highlight the importance of associating risk factors in the preclinical investigation of age-related cerebrovascular diseases physiopathology and potential therapies.

Assuntos

Envelhecimento/fisiologia , Isquemia Encefálica/patologia , Artéria Carótida Interna/patologia , Cognição/fisiologia , Amnésia Retrógrada/fisiopatologia , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/mortalidade , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/patologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/patologia , Ratos Wistar

RESUMO

4-Hydroxy-3-methoxy-acetophenone (apocynin) is a naturally occurring methoxy-substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI)-induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight-arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX-42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long-term protective effects of apocynin may involve inhibition of the glial response.

Assuntos

Acetofenonas/uso terapêutico , Hipocampo/metabolismo , Ataque Isquêmico Transitório/metabolismo , Transtornos da Memória/metabolismo , Neuroglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Acetofenonas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Hipocampo/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/psicologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/psicologia , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar

RESUMO

The effect of the oral administration of blood glucose precursors on glycemia recovery and liver glucose production in fasted mice subjected to insulin-induced hypoglycemia (IIH) was investigated. IIH was obtained with increasing doses (from 0.5 to 2.0 U·kg(-1)) of intraperitoneal regular insulin where glycemia was evaluated from 0 to 300 min after insulin injection. The dose of 1.0 U·kg(-1) showed the best results, that is, a clear glycemia recovery phase without convulsions or deaths. Thus, this dose was used in all experiments. Afterwards, mice submitted to IIH received orally by gavage: saline (control group), glucose (100 mg·kg(-1)), glycerol (100 mg·kg(-1)), lactate (100 mg·kg(-1)), alanine (100 mg·kg(-1)), or glutamine (100 mg·kg(-1)). It was observed that glutamine was more effective in promoting glycemia recovery if compared with glucose, lactate, glycerol, or alanine. In agreement with these results, the best performance in terms of liver glucose production was obtained when glutamine was used as glucose precursors. These results open perspectives for clinical studies to investigate the impact of oral administration of gluconeogenic amino acids to promote glycemia recovery during hypoglycemia.