Probucol mitigates streptozotocin-induced cognitive and biochemical changes in mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss and cognitive impairments. Although AD is the most prevalent aging-related neurodegenerative disease, therapeutic strategies remain palliative. Recent studies have shown that probucol presents neuroprotective effects in experimental models of neurodegenerative disease. The present study aimed to investigate the potential protective effects of probucol against streptozotocin (STZ)-induced cognitive impairment and hippocampal biochemical changes (oxidative stress-related parameters, acetylcholinesterase (AChE) activity, cholesterol levels and ß-secretase (BACE) protein levels) in mice. Adult Swiss mice received STZ [150 µg/bilateral, i.c.v.], and treated daily with probucol (≅10 mg/kg/day, in drinking water, for 5 weeks,). Twenty-one days after i.c.v. administrations, STZ-infused animals displayed significant deficits in cognition (evaluated in the displaced and new object recognition tasks), which were paralleled by a significant increase in hippocampal AChE activity. Moreover, STZ-infused mice showed increased levels of BACE and decreased glutathione reductase (GR) activity in the hippocampus compared with the control group. Probucol treatment significantly protected against the behavioral and hippocampal biochemical changes induced by STZ. However, it was unable to prevent STZ-induced increase of hippocampal BACE levels and did not change hippocampal cholesterol levels. It is noteworthy that probucol treatment increased the glutathione peroxidase (GPx) activity per se independent of STZ injection. The present findings are the first to show that i.c.v. STZ infusions are able to increase hippocampal BACE expression. Moreover, the results also show that probucol can counteract STZ-induced cognitive impairments and biochemical parameters independently of potential modulator effects toward BACE levels. The study is the first to report the protective effects of probucol against STZ-induced biochemical hippocampal changes and behavioral impairments, rendering this compound a promising molecule for further pharmacological studies on the search for therapeutic strategies to treat or prevent AD.

Hypercholesterolemia as a risk factor for depressive disorder?

AIMS: Epidemiological findings demonstrated that increased plasma cholesterol levels are frequently observed in depressive patients. In this regard, there is enhancing evidence that hypercholesterolemia is associated with impairment of brain function. Recently, we demonstrated that low-density lipoprotein receptor knockout (LDLr(-/-)) mice- a widely used rodent model of familial hypercholesterolemia - exhibited memory deficits and cortico-cerebral mitochondrial dysfunction. In this study, we aimed to assess the hypercholesterolemic mice in predictive tasks for depressive-like behavior. METHODS: Adult wild type C57BL/6 and LDLr (-/-) mice were evaluated in two tests for depressive like behavior, the splash test and forced swimming test. In addition, the activity of monoamine oxidase isoforms and the mRNA levels of hemeoxygenase-1 were assessed in the hippocampus and cerebral cortex of C57BL/6 and LDLr (-/-) mice. Finally, the blood-brain-barrier (BBB) permeability was investigated using the AQP-4 immunofluorescence staining in the mice hippocampus. RESULTS: The LDLr (-/-) mice showed a significant reduction in the grooming time in the splash test and increased immobility time in the forced swimming test, and both parameters were reversed by fluoxetine antidepressant treatment (10mg/kg, 7 days, o.g.). Interestingly, the depressive like behavior of LDLr (-/-) mice was associated with increased activity of monoamine oxidase A, decreased hemeoxygenase-1 mRNA levels and increase of BBB permeability in the hippocampus. CONCLUSIONS: Overall, these data provide new evidence that hypercholesterolemia could trigger brain alterations involved in depressive disorders.

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice.

L-DOPA alleviates the motor symptoms of Parkinson's disease, but its long-term use is associated with undesirable dyskinesia. We now tested whether exercise can attenuate this L-DOPA-induced dyskinesia (LID). We tested the effects of exercise on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. Animals were treated with L-DOPA/benserazide (25/12.5 mg/kg, i.p.) without and with possibility to exercise (running wheel) during 2 weeks. Exercise drastically prevented the development of LID, and its associated aberrant striatal signaling, namely the hyperphosphorylation of dopamine and cAMP-regulated phosphoprotein 32 kDa protein and c-Fos expression. Our results indicate that exercise can partially prevent the development of LID through the normalization of striatopallidal dopaminergic signaling.

Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress.

Convergent epidemiological, clinical, and experimental findings indicate that hypercholesterolemia contributes to the onset of Alzheimer's disease (AD)-like dementia, but the exact underlying mechanisms remains unknown. In this study, we evaluated the cognitive performance of mice submitted to a model of hypercholesterolemia, as well as its relationship with mitochondrial dysfunction and oxidative stress, two key events involved in AD pathogenesis. Wild-type C57bl/6 or low density lipoprotein receptor (LDLr)-deficient mice were fed with either standard or cholesterol-enriched diet for a 4-week period and tested for spatial learning and memory in the object location task. LDLr⁻/⁻ mice displayed spatial learning and memory impairments regardless of diet. Moreover, LDLr⁻/⁻ mice fed cholesterol-enriched diet presented a significant decrease in the mitochondrial complexes I and II activities in the cerebral cortex, which were negatively correlated with respective blood cholesterol levels. Additionally, hypercholesterolemic LDLr⁻/⁻ mice presented a significant decrease in glutathione levels, about 40% increase in the thiobarbituric acid-reactive substances levels, as well as an imbalance between the peroxide-removing-related enzymes glutathione peroxidase/glutathione reductase activities in the cerebral cortex. These findings indicate a significant relationship between hypercholesterolemia, cognitive impairment, and cortico-cerebral mitochondrial dysfunctional/oxidative stress. Because of the involvement of such alterations in AD patients, our data render this mouse model of hypercholesterolemia a useful approach to comprehend the molecular events mediating AD pathogenesis.