Aerobic Training and Circulating Neurotrophins in Alzheimer's Disease Patients: A Controlled Trial.

OBJECTIVE: to verify the effects of aerobic exercise training in circulating BDNF, VEGF165 and IGF-1 plasma levels and cognitive function in Alzheimer's Disease (AD) patients. METHODS: 34 AD patients participated in the study, divided in two groups: Control Group (CG; n = 16) and Training Group (TG; n = 18 - Moderate aerobic training on the treadmill, three times a week, for 12 weeks). BDNF, VEGF165, and IGF-1 plasma levels were considered as a primary outcome. Secondary outcomes included cognitive functions and aerobic fitness. RESULTS: After 12 weeks, maintenance of executive functioning in the TG was found, yet no significant changes on circulating neurotrophins levels were identified. For aerobic fitness, there was an increment in TG group. CONCLUSION: Twelve weeks of aerobic training were neither effective in improving cognitive functioning significantly, nor influential on circulating neurotrophins levels in AD patients.

Circulating levels of vascular endothelial growth factor in patients with Alzheimer's disease: A case-control study.

BACKGROUND: Vascular endothelial growth factor (VEGF) and platelets seem to reflect the Alzheimer's disease (AD) associated either with vascular impairment or disease. This study aimed to compare the circulating levels of VEGF and platelets between AD patients and healthy older adults. METHODS: Seventy-two older adults, divided in 40 older adults (Clinical Dementia Rating Scale - CDR = 0); and 32 Alzheimer's disease patients (clinically diagnosed - CRD = 1) participated in the present study. The groups were paired by sex, age, comorbidities and educational level. The primary outcomes included circulating plasma VEGF and platelet levels obtained by blood collection. RESULTS: The VEGF levels were significantly different between the groups (p = 0.03), with having a large effect size ( η2 =18.15), in which the AD patients presented lower levels compared to healthy older adults. For platelets, the comparison showed a tendency to difference (p = 0.06), with a large effect size (η2 =12.95) between the groups. CONCLUSION: The VEGF levels and the platelet numbers were reduced in AD patients, suggesting that angiogenic factors could be modified due to AD.

Acute exercise increases circulating IGF-1 in Alzheimer's disease patients, but not in older adults without dementia.

OBJECTIVES: Increased Insulin-like growth factor I (IGF-1) has been associated with improvement of cognitive function in response to exercise. Evidences indicate a role for IGF-1 in beta-amyloid clearance and reducing hyperphosphorylation tau in Alzheimer's disease (AD). There is a need to investigate the IGF-1 response to exercise in AD patients due to well-known potential effects of exercise on IGF-1. The aim of this study was to examine circulating IGF-1 levels in AD patients and older adults without dementia after acute exercise and to verify the associations among cardiorespiratory fitness, cognition and IGF-1 levels. METHOD: Seventy-four older adults (40 older adults without dementia and 34 AD patients) participated in this study. The outcomes included IGF-1 plasma levels and performance in the submaximal exercise stress test. Secondary outcomes included cognitive functions, depressive symptoms, level of physical activity, insulin-resistance, and cholesterol. All participants performed the incremental test on a treadmill and IGF-1 was collected before and after the exercise. RESULTS: A tendency to the difference of baseline IGF-1 plasma levels between the groups was found. After the acute exercise AD patients also presented higher levels of circulating IGF-1 compared to the Older adults without dementia. Correlations among cardiorespiratory fitness and cognitive functions were found. CONCLUSION: The findings suggest that AD patients and older adults respond differently to acute exercise in terms of circulating IGF-1 levels. This response seems to indicate either an IGF-1 resistance or a compensatory exercise-induced to lower IGF-1 levels in AD patients. Cardiorespiratory fitness is associated with global cognition, executive function, attention and information processing speed.

Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and up-regulates hippocampal α7 nACh receptors in mice.

BACKGROUND AND PURPOSE: Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4ß2*, α7 nicotinic acetylcholine (nAChR), µ-opioid (µ receptors) and D2 dopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. EXPERIMENTAL APPROACH: Male C57Bl/6J mice treated with nicotine (minipump, 24 mg·kg-1 ·day-1 ) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h·day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4ß2*, α7 nAChRs, µ receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. KEY RESULTS: Nicotine-treated mice undertaking 2 or 24 h·day-1 wheel running displayed a significant reduction in withdrawal symptom severity compared with the sedentary group. Wheel running induced a significant up-regulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected µ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4ß2* nAChR binding, irrespective of exercise regimen. CONCLUSIONS AND IMPLICATIONS: We demonstrated for the first time a profound effect of exercise on α7 nAChRs in nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise on the development of nicotine dependence. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

Effects of environmental enrichment upon ethanol-induced conditioned place preference and pre-frontal BDNF levels in adolescent and adult mice.

Environmental enrichment (EE) provides a non-pharmacological tool to alter drug-induced reward, yet its effects on ethanol-induced reward remain controversial. We analyzed adolescent vs. adult (mice) differences in the influence of EE on ethanol-induced conditioned place preference (CPP). The effects of these treatments on brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex were examined in a separate group of animals. Ethanol-induced CPP was found in adults, and it was similar in EE and in animals reared under standard housing conditions (SC). Adolescents kept under EE, but not those in SC, exhibited CPP. Among SC, but not among EE, adolescents, BDNF levels were significantly lower in those treated with ethanol than in those given vehicle. These results indicate that, compared to adults, adolescent exhibited reduced sensitivity to ethanol's rewarding effects, yet the youth but not the adults exhibited sensitivity to the promoting effect of EE upon CPP by ethanol. Ethanol significantly reduced BDNF levels in adolescents reared under standard housing conditions, but not in adult mice nor in adolescents given EE housing conditions. The present results add to the plethora of adolescent-specific responses to ethanol or to environmental stimuli that may put the youth at risk for escalation of ethanol intake.

Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease.

Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

A transcriptional study in mice with different ethanol-drinking profiles: possible involvement of the GABA(B) receptor.

Previous studies have suggested that γ-aminobutyric acid-B (GABA(B)) receptor agonists effectively reduce ethanol intake. The quantification using real-time polymerase chain reaction of Gabbr1 and Gabbr2 mRNA from the prefrontal cortex, hypothalamus, hippocampus, and striatum in mice exposed to an animal model of the addiction developed in our laboratory was performed to evaluate the involvement of the GABA(B) receptor in ethanol consumption. We used outbred, Swiss mice exposed to a three-bottle free-choice model (water, 5% v/v ethanol, and 10% v/v ethanol) that consisted of four phases: acquisition (AC), withdrawal (W), reexposure (RE), and quinine-adulteration (AD). Based on individual ethanol intake, the mice were classified into three groups: "addicted" (A group; preference for ethanol and persistent consumption during all phases), "heavy" (H group; preference for ethanol and a reduction in ethanol intake in the AD phase compared to AC phase), and "light" (L group; preference for water during all phases). In the prefrontal cortex in the A group, we found high Gabbr1 and Gabbr2 transcription levels, with significantly higher Gabbr1 transcription levels compared with the C (ethanol-naive control mice), L, and H groups. In the hippocampus in the A group, Gabbr2 mRNA levels were significantly lower compared with the C, L, and H groups. In the striatum, we found a significant increase in Gabbr1 transcription levels compared with the C, L, and H groups. No differences in Gabbr1 or Gabbr2 transcription levels were observed in the hypothalamus among groups. In summary, Gabbr1 and Gabbr2 transcription levels were altered in cerebral areas related to drug taking only in mice behaviorally classified as "addicted" drinkers, suggesting that these genes may contribute to high and persistent ethanol consumption.

GABA(B) receptor agonist only reduces ethanol drinking in light-drinking mice.

Baclofen, a GABA(B) agonist, reduces ethanol intake in animals and humans, but the contrary or no effect was also reported. Our previous study demonstrated that mice characterized as "loss of control over ethanol intake" had different Gabbr1 and Gabbr2 transcription levels, which express, respectively, the GABA(B1) and GABA(B2) subunits in brain areas related to addictive behavior. In the present study, we tested baclofen on ethanol intake in mice exposed to the free-choice paradigm. Adult male Swiss mice, individually housed, had free access to three bottles: ethanol (5% and 10%) and water. The protocol had four phases: acquisition (AC, 10 weeks), withdrawal (W, 4 cycles during 2 weeks of 2 day-free-choice and 2 day-only-water), reexposure (RE, 2 weeks), and adulteration of ethanol solutions with quinine (AD, 2 weeks). Mice characterized as "loss of control" (A, n=11, preference for ethanol in AC and maintenance of ethanol intake levels in AD), heavy (H, n=11, preference for ethanol in AC and reduction of ethanol intake levels in AD), and light (L, n=16, preference for water in all phases) drinkers were randomly distributed into two subgroups receiving either intraperitoneal injections of all doses of baclofen (1.25, 2.5, and 5.0mg/kg, given each dose twice in consecutive days) or saline, being exposed to free-choice. Fluid consumption was measured 24h later. Baclofen reduced ethanol intake in group L. In group H a reduction compared to AC was observed. Group A maintained their high ethanol intake even after baclofen treatment. Activation of the GABA(B) receptor depends on the precise balance between the GABA(B1) and GABA(B2) subunits, so the disproportionate transcription levels, we reported in group A, could explain this lack of response to baclofen. These data highlight the importance to test baclofen in individuals with different ethanol drinking profiles, including humans.

Environmental enrichment blocks ethanol-induced locomotor sensitization and decreases BDNF levels in the prefrontal cortex in mice.

The use of addictive drugs can lead to long-term neuroplastic changes in the brain, including behavioral sensitization, a phenomenon related to addiction. Environmental enrichment (EE) is a strategy used to study the effect of environment on the response to several manipulations, including treatment with addictive drugs. Brain-derived neurotrophic factor (BDNF) has been associated with behaviors related to ethanol addiction. The aim of the present study was to evaluate the effects of EE on ethanol-induced behavioral sensitization and BDNF expression. Mice were exposed to EE and then repeatedly treated with a low dose (1.8 g/kg) of ethanol. Another group of mice was first subjected to repeated ethanol treatment according to the behavioral sensitization protocol and then exposed to EE. Environmental enrichment prevented the development of ethanol-induced behavioral sensitization and blocked behavioral sensitization in sensitized mice. Both repeated ethanol and EE decreased BDNF levels in the prefrontal cortex but not in the hippocampus. However, BDNF levels were lower in ethanol-treated mice exposed to EE. These findings suggest that EE can act on the mechanisms implicated in behavioral sensitization, a model for drug-induced neuroplasticity and relapse. Additionally, EE alters BDNF levels, which regulate addiction-related behaviors.

Environmental modulation of ethanol-induced locomotor activity: Correlation with neuronal activity in distinct brain regions of adolescent and adult Swiss mice.

Drug abuse is a concerning health problem in adults and has been recognized as a major problem in adolescents. Induction of immediate-early genes (IEG), such as c-Fos or Egr-1, is used to identify brain areas that become activated in response to various stimuli, including addictive drugs. It is known that the environment can alter the response to drugs of abuse. Accordingly, environmental cues may trigger drug-seeking behavior when the drug is repeatedly administered in a given environment. The goal of this study was first to examine for age differences in context-dependent sensitization and then evaluate IEG expression in different brain regions. For this, groups of mice received i.p. ethanol (2.0 g/kg) or saline in the test apparatus, while other groups received the solutions in the home cage, for 15 days. One week after this treatment phase, mice were challenged with ethanol injection. Acutely, ethanol increased both locomotor activity and IEG expression in different brain regions, indistinctly, in adolescent and adult mice. However, adults exhibited a typical context-dependent behavioral sensitization following repeated ethanol treatment, while adolescent mice presented gradually smaller locomotion across treatment, when ethanol was administered in a paired regimen with environment. Conversely, ethanol-treated adolescents expressed context-independent behavioral sensitization. Overall, repeated ethanol administration desensitized IEG expression in both adolescent and adult mice, but this effect was greatest in the nucleus accumbens and prefrontal cortex of adolescents treated in the context-dependent paradigm. These results suggest developmental differences in the sensitivity to the conditioned and unconditioned locomotor effects of ethanol.