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The neurological involvement in acute liver failure (ALF) is characterized by arousal impairment with progression to coma. There is a growing body of evidence that neuroinflammatory mechanisms play a role in this process, including production of inflammatory cytokines and microglial activation. However, it is still uncertain whether brain-derived cytokines and glial cells are crucial to the pathophysiology of ALF at the early stage, before coma development. Here, we investigated the influence of cytokines and microglia in ALF-induced encephalopathy in mice as soon as neurological symptoms were identifiable. Behavior was assessed at 12, 24, 36 and 48 h post-injection of thioacetamide, a hepatotoxic drug, through locomotor activity by an open field test. Brain concentration of cytokines (TNF-α and IL-1β) and chemokines (CXCL1, CCL2, CCL3 and CCL5) were assessed by ELISA. Microglial activation in brain sections was investigated through immunohistochemistry, and cellular ultrastructural changes were observed by transmission electron microscopy. We found that ALF-induced animals presented a significant decrease in locomotor activity at 24 h, which was accompanied by an increase in IL-1β, CXCL1, CCL2, CCL3 and CCL5 in the brain. TNF-α level was significantly increased only at 36 h. Despite marked morphological changes in astrocytes and brain endothelial cells, no microglial activation was observed. These findings suggest an involvement of brain-derived chemokines and IL-1β in early pathophysiology of ALF by a mechanism independent of microglial activation. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To investigate the effect of 2 standardized exercise programs, muscle strength exercises (SE) and aerobic exercises (AE), on the plasma levels of brain-derived neurotrophic factor (BDNF) and depressive symptoms in 451 elderly women. Design: A randomized controlled trial. Setting: Belo Horizonte/MG–Brazil. Participants: Community-dwelling older women (N=451; age, 65–89y). Intervention: The participants were divided into 2 groups: SE and AE. Both protocols lasted 10 weeks, and 30 sessions (1-h sessions) in total were performed 3 times a week under the direct supervision of physical therapists. Main Outcome Measures: Plasma levels of BDNF (enzyme-linked immunosorbent assay) and depressive symptoms (Geriatric Depression Scale). Results: There was a significant difference for BDNF plasma levels between the SE and AE groups (P=.009). Post hoc analysis revealed a pre-post intervention difference in BDNF levels only for the SE group (P=.008). A statistically significant difference was found for the pre- and postintervention Geriatric Depression Scale scores in both groups (P=.001), showing that the effects of both exercise protocols were comparable regarding depressive symptoms (P=.185). Conclusions: The present findings have demonstrated the positive effect of muscle strengthening and aerobic intervention on depressive symptoms in community-dwelling elderly women. Interestingly, only SE significantly increased the plasma levels of BDNF in our sample. The positive effects of physical exercise on depressive symptoms in the elderly were not mediated by BDNF. [ABSTRACT FROM AUTHOR]

Abstract: Simão AP, Avelar NC, Tossige-Gomes R, Neves CD, Mendonça VA, Miranda AS, Teixeira MM, Teixeira AL, Andrade AP, Coimbra CC, Lacerda AC. Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis. Objective: To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis (OA). Design: Clinical, prospective, randomized, single-blinded study. Setting: Exercise physiology laboratory. Participants: Elderly subjects with knee OA (N=32) were divided into 3 groups: (1) squat exercises on a vibratory platform (platform group, n=11); (2) squat exercises without vibration (squat group, n=10); and (3) the control group (n=11). Interventions: The structured program of squat exercises in the platform and squat groups was conducted 3 times per week, on alternate days, for 12 weeks. Main Outcome Measures: Plasma soluble tumor necrosis factor-α receptors 1 (sTNFR1) and 2 (sTNFR2) were measured using immunoassays (the enzyme-linked immunosorbent assay method). The Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used to evaluate self-reported physical function, pain, and stiffness. The 6-minute walk test, the Berg Balance Scale, and gait speed were used to evaluate physical function. Results: In the platform group, there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 (P<.001 and P<.05, respectively) and self-reported pain (P<.05) compared with the control group, and there was an increase in balance (P<.05) and speed and distance walked (P<.05 and P<.001, respectively). In addition, the platform group walked faster than the squat group (P<.01). Conclusions: The results suggest that whole-body vibration training improves self-perception of pain, balance, gait quality, and inflammatory markers in elderly subjects with knee OA. [Copyright &y& Elsevier]

Objectives: To evaluate the usual gait speed of asymptomatic adult and elderly Brazilians with a 10-meter walk test and to compare the results with foreign reference values. Methods: Seventy-nine asymptomatic volunteers ≥40 years old of both genders were assessed. After anamnesis, anthropometry and the application of a habitual physical activity questionnaire, the volunteers were submitted to a 10-meter walk test at usual speed by means of which gait speed, the number of steps and length of stride were calculated. Results: Except for age, all study variables were significantly lower in women. Subjects ≥70 years old presented a significantly lower gait speed than subjects between 40 and 49 years old and between 50 and 59 in both men (1.09±0.18 m/s, 1.35±0.11 m/s and 1.34±0.22 m/s, respectively) and women (1.02±0,10 m/s, 1.27±0.20 m/s and 1.27±0,15 m/s), respectively). Gait speed showed moderate correlations with age (r=-0.41, p<0.001) and height (r=0.35, p=0.001). After multiple regression analysis, age and gender were selected as relevant attributes of gait speed in that they explained 24.6% of this variable. The gait speed values in this study were significantly lower than foreign reference values (p<0.05). Conclusions: The gait speed presented age-related decline and values significantly lower than those described for foreign populations. This finding indicates the need for comprehensive investigation of gait speed reference values for the Brazilian population. [ABSTRACT FROM AUTHOR]

Abnormal calcium influx and glutamatergic excitotoxicity have been extensively associated with neuronal death in Huntington's disease (HD), a genetic movement disorder. Currently, there is no effective treatment for this fatal condition. The neurotoxin Phα1β has demonstrated therapeutic effects as a calcium channel blocker, for example during pain control. However, little is known about its neuroprotective effect in HD. Herein, we investigated if Phα1β is effective in inhibiting neuronal cell death in the BACHD mouse model for HD. We performed intrastriatal injection of Phα1β in WT and BACHD mice. No side effects or unusual behaviors were observed upon Phα1β administration. Using three different motor behavior tests, we observed that injection of the toxin in BACHD mice greatly improved the animals' motor-force as seen in the Wire-hang test, and also the locomotor performance, according to the Open field test. NeuN labeling for mature neuron detection revealed that Phα1β toxin promoted neuronal preservation in the striatum and cortex, when injected locally. Intrastriatal injection of Phα1β was not able to preserve neurons from the spinal cord and also not revert muscle atrophy in BACHD mice. Finally, we observed that Phα1β might, at least in part, exert its protective effect by decreasing L-glutamate, measured in cerebrospinal fluid. Our data provide evidence of a novel neuroprotector effect of Phα1β, paving a path for the development of new approaches to treat HD motor symptoms. [ABSTRACT FROM AUTHOR]

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CB 1 R). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling. Male C57BL/6J mice were tested for contextual fear memory after low-, moderate-, or high-intensity shock protocols. The selective TRPV1 blockers SB366791 (1-10 nmol) and 6-I-NC (2 nmol) were infused via intra-dorsal hippocampus before the retrieval test session. The local levels of endocannabinoids and Arc and Zif268 mRNAs, involved in synaptic plasticity and memory, were quantified. First, both TRPV1 blockers reduced memory retrieval in animals exposed to moderate or high (but not low) intensity training protocols. In the second series of results, the magnitude of the freezing responses positively correlated with the hippocampal anandamide levels; TRPV1 and CB 1 R were found co-localized in this brain region; and the CB 1 R antagonist, AM251, prevented the effects of SB366791. Thus, endocannabinoid signaling possibly mediates the effects of TRPV1 blockers. Finally, inhibition of memory retrieval by TRPV1 blockers increased Arc and Zif268 mRNAs and impaired fear memory reinstatement. In conclusion, the modulation of fear memories by dorsal hippocampal TRPV1 channels may depend on the aversive stimulus intensity and occur via anandamide/CB 1 signaling. Moreover, TRPV1 blockers promote Arc and Zif268 transcription, with subsequent attenuation of aversive memory reinstatement. • TRPV1 blockage in the hippocampus inhibits the retrieval of contextual fear memory. • The effects of TRPV1 blockers depend on the intensity of the aversive stimulus. • Retrieval of contextual fear memory increases hippocampal anandamide levels. • The effects of TRPV1 blockers depend on local anandamide/CB 1 R signalling. [ABSTRACT FROM AUTHOR]

Abstract: Background: The Glial Cell-line derived neurotrophic factor (GDNF) is part of the TGF-β superfamily and is abundantly expressed in the central nervous system. Changes in GDNF homeostasis have been reported in affective disorders. Aim: To assess serum GDNF concentration in elderly subjects with late-life depression, before antidepressant treatment, as compared to healthy elderly controls. Methods: Thirty-four elderly subjects with major depression and 37 age and gender-matched healthy elderly controls were included in this study. Diagnosis of major depression was ascertained by the SCID interview for DSM-IV and the severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HDRS-21). Serum GDNF concentration were determined by sandwich ELISA. Results: Patients with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 scores (r = −0.343, p = 0.003). Discussion: Our data provide evidence that GDNF may be a state marker of depressive episode in older adults. Changes in the homeostatic control of GDNF production may be a target to development of new antidepressant strategies. [Copyright &y& Elsevier]

COVID-19 affects primarily the lung. However, several other systemic alterations, including muscle weakness, fatigue and myalgia have been reported and may contribute to the disease outcome. We hypothesize that changes in the neuromuscular system may contribute to the latter symptoms observed in COVID-19 patients. Here, we showed that C57BL/6J mice inoculated intranasally with the murine betacoronavirus hepatitis coronavirus 3 (MHV-3), a model for studying COVID-19 in BSL-2 conditions that emulates severe COVID-19, developed robust motor alterations in muscle strength and locomotor activity. The latter changes were accompanied by degeneration and loss of motoneurons that were associated with the presence of virus-like particles inside the motoneuron. At the neuromuscular junction level, there were signs of atrophy and fragmentation in synaptic elements of MHV-3-infected mice. Furthermore, there was muscle atrophy and fiber type switch with alteration in myokines levels in muscles of MHV-3-infected mice. Collectively, our results show that acute infection with a betacoronavirus leads to robust motor impairment accompanied by neuromuscular system alteration. • Betacoronavirus infection causes motor impairment. • Motoneuron loss is caused by betacoronavirus infection. • Betacoronavirus infection causes neuromuscular junction degeneration. • Skeletal muscle atrophy is developed after betacoronavirus infection. [ABSTRACT FROM AUTHOR]

The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu 5 receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu 5 receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu 5 receptor knockout (mGluR5−/−) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5−/−/BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu 5 receptor has a role in brain aging. We demonstrated that mGluR5−/− mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5−/−/BACHD mice. In addition, ablation of mGlu 5 receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5−/− mice induced microglia activation, evidenced by increased CD68 expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu 5 receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu 5 receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS). • mGluR5−/− mice exhibit age-dependent neuronal cell loss to the same levels as that of a mouse model of Huntington's disease. • mGlu 5 receptor knockout triggers gliosis and microglia activation in the cortex in an age-dependent manner. • The presence of htt and ablation of mGlu 5 receptor decrease expression of fractalkine in aged mice. [ABSTRACT FROM AUTHOR]

Inhibition of dopamine transporter (DAT) by GBR12909 has been proposed as a pharmacological model of mania related to bipolar disorder (BD). Here we tested the hypothesis that GBR12909 injection impairs habituation and induces hyperlocomotion in mice, along with changes in cytokines and neurotrophic factors levels, as observed in BD patients. We also tested if lithium carbonate, sodium valproate and aripiprazole prevent GBR12909-induced locomotion. Male Swiss mice received GBR12909 (15 mg/kg) injections and locomotor responses were quantified in an open field. Cytokines and neurotrophic factors levels were assessed in the prefrontal cortex, striatum and hippocampus 30 min and 24 h after injections. Pre-treatments with lithium, valproate or aripiprazole were performed with single and repeated injection protocols. GBR12909 prevented motoric habituation and increased basal locomotion in habituated mice in the open field. This compound also induced changes in IL-2 and BDNF levels in prefrontal cortex; IL-2, IL-4 and IL-10 in striatum; and IL-10, IL-4, IFN-γ and NGF in hippocampus. GBR12909-induced hyperlocomotion was attenuated by lithium (12.5–100 mg/kg), but not valproate (75–300 mg/kg), and prevented by aripiprazole (0.1–10 mg/kg). Repeated injections of these drugs (twice a day for 3 days), however, failed to inhibit hyperlocomotion. The main limitations of the protocols in this study are the analysis of locomotion as the only behavioral parameter, changes in immune factors that may overlap with other psychiatric disorders and the lack chronic drug injections. Despite of these limitations, this study adds to previous literature suggesting DAT inhibition as a potential animal model of mania related to BD. [ABSTRACT FROM AUTHOR]

Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes for memory consolidation related to place preference behavior underlying cocaine administration in mice. Conditioned place preference (CPP) is a protocol extensively used to study the rewarding and/or aversive motivational effects of drug abuse in rodents, reproducing cocaine-seeking behavior in humans. Besides the variety of apparatus used in the CPP protocol, whether different types of apparatus are able to induce the same conditioned behavior response and neurobiological changes remains to be fully explored. We hypothesize that the immune response is involved in the cocaine-induced CPP and that the type of apparatus might influence this response. Herein, two- and three-compartment apparatuses were tested using the behavioral model of CPP. Cocaine-induced CPP was demonstrated in both apparatuses. However, mice injected with cocaine had decreased levels of IL-1β, IL-6, IL-10, and GDNF in the pre-frontal cortex, and decreased CX3CL1 in the striatum, in the CPP protocol using three compartments compared to controls. While similar levels were seen in the CPP protocol using two compartments. In conclusion, the current study demonstrated that the type of apparatus might influence the investigation of neurobiological mechanisms associated with cocaine-induced CPP. Our data also suggest that the three compartment-apparatus seems to be a more appropriate model to investigate the neuroinflammatory response related to cocaine addiction. • Peripheral administration of cocaine induces CPP behavior in mice. • The three-compartment apparatus alters brain levels of cytokines. • The three-compartment apparatus alters brain levels of neurotrophic factors. • Cytokines and Neurotrophic Factors play a role in Cocaine-induced CPP behavior. [ABSTRACT FROM AUTHOR]