Neurodegeneration and glial morphological changes are both prevented by TRPM2 inhibition during the progression of a Parkinson's disease mouse model.

Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-3ß/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment.

Lithium and disease modification: A systematic review and meta-analysis in Alzheimer's and Parkinson's disease.

The role of lithium as a possible therapeutic strategy for neurodegenerative diseases has generated scientific interest. We systematically reviewed and meta-analyzed pre-clinical and clinical studies that evidenced the neuroprotective effects of lithium in Alzheimer's (AD) and Parkinson's disease (PD). We followed the PRISMA guidelines and performed the systematic literature search using PubMed, EMBASE, Web of Science, and Cochrane Library. A total of 32 articles were identified. Twenty-nine studies were performed in animal models and 3 studies were performed on human samples of AD. A total of 17 preclinical studies were included in the meta-analysis. Our analysis showed that lithium treatment has neuroprotective effects in diseases. Lithium treatment reduced amyloid-ß and tau levels and significantly improved cognitive behavior in animal models of AD. Lithium increased the tyrosine hydroxylase levels and improved motor behavior in the PD model. Despite fewer clinical studies on these aspects, we evidenced the positive effects of lithium in AD patients. This study lends further support to the idea of lithium's therapeutic potential in neurodegenerative diseases.

Pathophysiological aspects of neonatal anoxia and temporal expression of S100ß in different brain regions.

The aim of this study was to investigate the temporal variations of S100ß in the hippocampus, cerebellum and cerebral cortex of neonatal rats (Wistar strain) under anoxic conditions. Real-time PCR and western blotting techniques were used for gene expression and protein analysis. Animals were divided into two groups, a control group and an anoxic group, and further separated at different time points for analysis. After anoxia, S100ß gene expression showed a significant peak in the hippocampus and cerebellum after 2 h, followed by a decline compared to the control group at other time points. The increased gene expression in these regions was also accompanied by an increase in S100ß protein levels in the anoxia group, observable 4 h after injury. In contrast, S100ß mRNA content in the cerebral cortex never exceeded control values at any time point. Similarly, the protein content of S100ß in the cerebral cortex did not show statistically significant differences compared to control animals at any assessment time point. These results suggest that the production profile of S100ß differs by brain region and developmental stage. The observed differences in vulnerability between the hippocampus, cerebellum and cerebral cortex may be attributed to their distinct developmental periods. The hippocampus and cerebellum, which develop earlier than the cerebral cortex, showed more pronounced effects in response to anoxia, which is supported by the gene expression and protein content in this study. This result reveals the brain region-dependent nature of S100ß as a biomarker of brain injury.

Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation.

Diabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.

The transient receptor potential melastatin 2: a new therapeutical target for Parkinson's disease?

The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca2+ influx that alters cell homeostasis and promotes cell death. The role of transient receptor potential melastatin 2 in neurodegenerative diseases, including Alzheimer's disease and ischemia, has already been described and reviewed. However, data on transient receptor potential melastatin 2 involvement in Parkinson's disease pathology has emerged only in recent years and the issue lacks review studies that focus specifically on this topic. The present review aims to elucidate the role of the transient receptor potential melastatin 2 channel in Parkinson's disease by reviewing, summarizing, and discussing the in vitro, in vivo, and human studies published until August 2022. Here we describe fourteen studies that evaluated the transient receptor potential melastatin 2 channel in Parkinson's disease. The Parkinson's disease model used, transient receptor potential melastatin 2 antagonist and genetic approaches, and the main outcomes reported were discussed. The studies described transient receptor potential melastatin 2 activation and enhanced expression in different Parkinson's disease models. They also evidenced protective and restorative effects when using transient receptor potential melastatin 2 antagonists, knockout, or silencing. This review provides a literature overview and suggests where there is a need for more research. As a perspective point, this review shows evidence that supports transient receptor potential melastatin 2 as a pharmacological target for Parkinson's disease in the future.

Microglial depletion exacerbates motor impairment and dopaminergic neuron loss in a 6-OHDA model of Parkinson's disease.

6-hydroxydopamine (6-OHDA) is a common neurotoxin used to induce Parkinson's disease (PD) in mice, exerting neurotoxic effects through the production of reactive oxygen species and microglial activation. However, the role of microglia in PD is still not clear, with contradictory reports showing neuroprotection or exacerbation of neuronal death. Microglial depletion aggravates motor coordination impairments and reduces tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Moreover, MeCP2 and Adora1 genes expression were downregulated, suggesting they may be involved in the neurodegenerative process. This study highlights that microglia plays a protective role in dopaminergic neuron survival during the initial phase of PD, and the investigation of the mechanisms of this effect in future studies will help elucidate the pathophysiology of PD.

The Symbiotic Effect of a New Nutraceutical with Yeast ß-Glucan, Prebiotics, Minerals, and Silybum marianum (Silymarin) for Recovering Metabolic Homeostasis via Pgc-1α, Il-6, and Il-10 Gene Expression in a Type-2 Diabetes Obesity Model.

The use of natural products and derivatives for the prevention and control of non-communicable chronic diseases, such as type-2 diabetes (T2D), obesity, and hepatic steatosis is a way to achieve homeostasis through different metabolic pathways. Thus, male C57BL/6 mice were divided into the following groups: high-fat diet (HFD) vehicle, HFD + Supplemented, HFD + Supplemented_S, and isolated compounds. The vehicle and experimental formulations were administered orally by gavage once a day over the four weeks of the diet (28 consecutive days). We evaluated the energy homeostasis, cytokines, and mitochondrial gene expression in these groups of mice. After four weeks of supplementation, only the new nutraceutical group (HFD + Supplemented) experienced reduced fasting glycemia, insulin, HOMA index, HOMA-ß, dyslipidemia, ectopic fat deposition, and hepatic fibrosis levels. Additionally, the PPARγ coactivator 1 α (Pgc-1α), interleukin-6 (Il-6), and interleukin-10 (Il-10) gene expression were augmented, while hepatic steatosis decreased and liver parenchyma was recovered. The glutathione-S-transferase activity status was found to be modulated by the supplement. We discovered that the new nutraceutical was able to improve insulin resistance and hepatic steatosis mainly by regulating IL-6, IL-10, and Pgc-1α gene expression.

Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer's Disease Rat Model: A Proof-of-Concept Study.

An early and persistent sign of Alzheimer's disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg-STZ-cannabidiol) or saline (STZ-saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ-saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ-cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ-cannabidiol animals. In addition, STZ-cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.

Inhibition of TRPM2 by AG490 Is Neuroprotective in a Parkinson's Disease Animal Model.

Parkinson's disease (PD) is characterized by motor impairment and dopaminergic neuronal loss. There is no cure for the disease, and treatments have several limitations. The transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, has been reported to be upregulated in neuronal death. However, there are no in vivo studies evaluating TRPM2's role and neuroprotective effects in PD. Here, we test the hypothesis that TRPM2 is upregulated in the 6-hydroxydopamine (6-OHDA) mouse model of PD and that its inhibition, by the AG490, is neuroprotective. For that, AG490 or vehicle were intraperitoneally administered into C57BL/6 mice. Mice then received 6-OHDA into the right striatum. Motor behavior assessments were evaluated 6, 13, and 20 days after surgery using the cylinder and apomorphine-induced rotational testes, and 7, 14, and 21 days after surgery using rotarod test. Brain samples of substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry and immunoblotting on days 7 and 21. We showed that TRPM2 protein expression was upregulated in 6-OHDA-treated animals. In addition, AG490 prevented dopaminergic neuron loss, microglial activation, and astrocyte reactivity in 6-OHDA-treated animals. The compound improved motor behaviors and Akt/GSK-3ß/caspase-3 signaling. We conclude that TRPM2 inhibition by AG490 is neuroprotective in the 6-OHDA model and that the TRPM2 channel may represent a potential therapeutic target for PD.

Neuroplasticity induced by the retention period of a complex motor skill learning in rats.

Learning complex motor skills is an essential process in our daily lives. Moreover, it is an important aspect for the development of therapeutic strategies that refer to rehabilitation processes since motor skills previously acquired can be transferred to similar tasks (motor skill transfer) or recovered without further practice after longer delays (motor skill retention). Different acrobatic exercise training (AE) protocols induce plastic changes in areas involved in motor control and improvement in motor performance. However, the plastic mechanisms involved in the retention of a complex motor skill, essential for motor learning, are not well described. Thus, our objective was to analyze the brain plasticity mechanisms involved in motor skill retention in AE . Motor behavior tests, and the expression of synaptophysin (SYP), synapsin-I (SYS), and early growth response protein 1 (Egr-1) in brain areas involved in motor learning were evaluated. Young male Wistar rats were randomly divided into 3 groups: sedentary (SED), AE, and AE with retention period (AER). AE was performed three times a week for 8 weeks, with 5 rounds in the circuit. After a fifteen-day retention interval, the AER animals was again exposed to the acrobatic circuit. Our results revealed motor performance improvement in the AE and AER groups. In the elevated beam test, the AER group presented a lower time and greater distance, suggesting retention period is important for optimizing motor learning consolidation. Moreover, AE promoted significant plastic changes in the expression of proteins in important areas involved in control and motor learning, some of which were maintained in the AER group. In summary, these data contribute to the understanding of neural mechanisms involved in motor learning in an animal model, and can be useful to the construction of therapeutics strategies that optimize motor learning in a rehabilitative context.

Association between thyroid function and Alzheimer's disease: A systematic review.

Alterations in metabolic parameters have been associated with an increased risk of dementia, among which thyroid function has gained great importance in Alzheimer's disease (AD) pathology in recent years. However, it remains unclear whether thyroid dysfunctions could influence and contribute to the beginning and/or progression of AD or if it results from AD. This systematic review was conducted to examine the association between thyroid hormone (TH) levels and AD. Medline, ISI Web of Science, EMBASE, Cochrane library, Scopus, Scielo, and LILACS were searched, from January 2010 to March 2020. A total of 17 articles were selected. The studies reported alterations in TH and circadian rhythm in AD patients. Behavior, cognition, cerebral blood flow, and glucose consumption were correlated with TH deficits in AD patients. Whether thyroid dysfunctions and AD have a cause-effect relationship was inconclusive, however, the literature was able to provide enough data to corroborate a relationship between TH and AD. Although further studies are needed in this field, the current systematic review provides information that could help future investigations.

Active lifestyle enhances protein expression profile in subjects with Lewy body pathology.

Clinical trials of the effects of physical activity have reported improvements in symptoms and quality of life in patients with Parkinson's disease (PD). Additionally, morphological brain changes after exercising were reported in PD animal models. However, these lifestyle-related changes were not evaluated in postmortem brain tissue. OBJECTIVE: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules - MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. METHODS: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Aging Studies were classified into active (n=12) and non-active (n=12) groups, according to physical activity lifestyle, and paired by age, sex and Braak staging. Substantia nigra and basal ganglia were evaluated. RESULTS: Groups were not different in terms of age or gender and had similar PD neuropathological burden (p=1.00). We observed higher TH expression in the active group in the substantia nigra and the basal ganglia (p=0.04). Astrocytes was greater in the non-active subjects in the midbrain (p=0.03) and basal ganglia (p=0.0004). MAP2 levels were higher for non-active participants in the basal ganglia (p=0.003) and similar between groups in the substantia nigra (p=0.46). Neurofilament levels for non-active participants were higher in the substantia nigra (p=0.006) but not in the basal ganglia (p=0.24). CONCLUSION: Active lifestyle seems to promote positive effects on brain by maintaining dopamine synthesis and structural protein expression in the nigrostriatal system and decrease astrogliosis in subjects with the same PD neuropathology burden.

Estudos dos efeitos da atividade física relataram melhora nos sintomas e na qualidade de vida de pacientes com doença de Parkinson (DP). Além disso, alterações morfológicas do cérebro após o exercício físico foram relatadas em modelos animais da DP. No entanto, essas mudanças relacionadas ao estilo de vida não foram avaliadas em tecido cerebral post-mortem. OBJETIVO: Avaliar a expressão de astrócitos, tirosina hidroxilase (TH) e a expressão de proteínas estruturais (neurofilamentos e microtúbulos ­ MAP2) por imuno-histoquímica, em amostras cerebrais post-mortem de indivíduos com corpos de Lewy. MÉTODOS: Amostras com estágio de Braak para DP≥III, classificação neuropatológica, fornecidas pelo biobanco de estudos do envelhecimento foram classificadas em grupos ativos (n=12) e não ativos (n=12), de acordo com o estilo de vida (atividade física), e pareados por idade, sexo e estadiamento de Braak. Analisou-se a substância negra e gânglios da base. RESULTADOS: Idade, sexo e classificação para DP foram semelhantes (p=1,00). Observou-se maior expressão de TH no grupo ativo (p=0,04). Amostras de não ativos revelaram maior expressão de astrócitos no mesencéfalo (p=0,03) e nos gânglios da base (p=0,0004); MAP2 nos gânglios da base (p=0,003); os níveis de neurofilamentos foram maiores na substância negra (p=0,006). CONCLUSÃO: O estilo de vida ativo parece promover efeitos positivos no cérebro, mantendo a síntese de dopamina e a expressão estrutural de proteínas no sistema nigrostriatal e com diminuição da ativação de astrócitos em indivíduos com a mesma classificação neuropatológica para a DP.

Involvement of substance P, osteopontin and satellite glial cells on photobiomodulation-induced antinociceptive effect in an experimental model of dentin hypersensitivity.

The aim of this work was to investigate the involvement of substance P (SP), osteopontin (OPN), and satellite glial cells (SGC) on photobiomodulation-induced (PBM) antinociceptive effect in an experimental model of dentin hypersensitivity (DH). Rats ingested isotonic drink (ID, pH 2.87) for 45 consecutive days and after this period received PBM irradiation at λ660 nm or λ808 nm (1 J, 3.5 J/cm2, 100 mW, 10 s, 0.028 cm2, continuous wave, 3 consecutive daily sessions), and were evaluated for nociceptive behavior 24, 48, 72 h, and 14 days after laser treatments. ID ingestion induced an increase on thermal sensitivity of DH characteristics in rats that was completely reversed by PBM treatment at both 660 and 808 nm. Immunohistochemical analysis revealed increased SP expression at both dentin-pulp complex (DPC) and trigeminal ganglia (TG) of DH-rats which did not occur in PBM groups by PBM treatment. Also, the increase of glial fibrillary acidic protein (GFAP) observed in the TG of DH-rats was also reversed by PBM treatment. Finally, PBM at both 660 and 808 nm increased OPN expression in the dentin-pulp complex of DH-rats after 14 days of PBM treatment. All in all, this data demonstrates that PBM reverses nociception in a DH experimental model by inhibiting neurogenic inflammation and inducing a regenerative response.

Physical exercise protects against mitochondria alterations in the 6-hidroxydopamine rat model of Parkinson's disease.

Parkinson's disease (PD) is typicaly caractherized by loss of dopaminergic neurons, as well as the presence of mitochondrial impairments. Although physical exercise is known to promote many beneficial effects in healthy subjects, such as enhancing mitocondrial biogenesis and function, it is not clear if these effects are evident after exercise in individuals with PD. The aim of this study was to investigate the effects of two different protocol durations on motor behavior (aphomorphine and gait tests), mitochondrial biogenesis signaling (PGC-1α, NRF-1 and TFAM), structure (oxidative phosphorylation system protein levels) and respiratory chain activity (complex I) in a unilateral PD rat model. For this, male Wistar rats were injected with 6-hydroxydopamine unilaterally into the striatum and submitted to an intermitent moderate treadmill exercise for one or four weeks. In the gait test, only stride width data revealed an improvement after one week of exercise. On the other hand, after 4 weeks of the exercise protocol all gait parameters analyzed and the aphomorphine test demonstrated a recovery. Analysis of protein revealed that one week of exercise was able to prevent PGC-1α and NRF-1 expression decrease in PD animals. In addition, after four weeks of physical exercise, besides PGC-1α and NRF-1, reduction in TFAM and complex I protein levels and increased complex I activity were also prevented in PD animals. Thus, our results suggest a neuroprotective and progressive effect of intermittent treadmill exercise, which could be related to its benefits on mitochondrial biogenesis signaling and respiratory chain modulation of the dopaminergic system in PD.

Oral treatment with royal jelly improves memory and presents neuroprotective effects on icv-STZ rat model of sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function. Intracerebroventricular injection of streptozotocin (icv-STZ) has been used as an experimental model of Sporadic AD (SAD) in rodents and represents a promising tool for etiopathogenic analysis and evaluation of new therapeutic proposals for AD. The icv-STZ model shows many aspects of SAD abnormalities, resulting in decreased brain glucose and energy metabolism, cognitive impairment, oxidative stress, neuronal loss, and amyloid angiopathy. Royal jelly (RJ), a substance produced by worker honeybees of the Apis mellifera species, has been popularly used for more than 30 years in areas related to health eating and natural medicine. Researches indicate that RJ has a several pharmacological activities, including neuroprotective and improvement of cognitive function. The objective of this study was to investigate the effects of oral treatment with royal jelly during 2 weeks in Wistar rats submitted to icv-STZ on a working memory and neuroprotection, as evaluated by neurogenesis, neurodegeneration and oxidative stress. In this study, icv-STZ injection induced deleterious effects in the hippocampus, associated with cognitive impairments, and developed marked neurodegeneration, besides the reduction of neurogenesis and increased oxidative stress. On the other hand, RJ long-term oral administration induced beneficial effects in animals injured by icv-STZ injection, increasing retention time for working spatial memory, reducing neurodegeneration and oxidative stress level and increasing the proliferation of new neurons in the hippocampus. Thus, RJ promotes beneficial effects on cognitive functions and exhibits a neuroprotective action in the STZ experimental model of SAD.

Impairment of PGC-1α-mediated mitochondrial biogenesis precedes mitochondrial dysfunction and Alzheimer's pathology in the 3xTg mouse model of Alzheimer's disease.

Impairment of mitochondrial biogenesis and mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). However, the extent to which the impairment of mitochondrial biogenesis influences mitochondrial dysfunction at the onset and during progression of AD is still unclear. Our study demonstrated that the protein expression pattern of the transcription factor pCREB/CREB, together with the protein expression of PGC-1α, NRF1 and TFAM are all significantly reduced in early ages of 3xTg-AD mice. We also found reduced mRNA expression levels of PKAC-α, CREB, PGC-1α, NRF1, NRF2 and TFAM as early as 1 month-of-age, an age at which there was no significant Aß oligomer deposition, suggesting that mitochondrial biogenesis is likely impaired in ages preceding the development of the AD pathology. In addition, there was a decrease in VDAC2 expression, which is related to mitochondrial content and mitochondrial function, as demonstrated by protein expression of complex IV, as well as complex II + III, and complex IV activities, at later ages in 3xTg-AD mice. These results suggest that the impairment in mitochondrial biogenesis signaling mediated by PGC-1α at early ages of the AD mice model likely resulted in mitochondrial dysfunction and manifestation of the AD pathology at later ages. Taken together, enhancing mitochondrial biogenesis may represent a potential pharmacological approach for the treatment of AD.

Retrieval of contextual aversive memory and induction of Zenk expression in the hippocampus of pigeons.

The hippocampus has a fundamental role in many learning and memory processes, which include the formation and retrieval of context-fear associations, as evidenced by studies in rodents and birds. The present paper has analyzed contextual memory and Zenk expression in the hippocampus of the pigeon after fear conditioning. Pigeons were trained under four conditions: with 3 tone-shock associations (Paired), with shock and tone presented randomly (Unpaired), with exposure to the experimental chamber without stimulation (Control) and with only daily handling (Naive). The testing was conducted 24 h after training. All sessions were digitally recorded. The level of freezing expressed by the Paired and Unpaired groups differed significantly from that of the control group during both training and test sessions. Pigeons from the Paired group revealed a significantly greater density of Zenk positive nuclei in the ventromedial region of the hippocampus than did the Unpaired, Control and Naive groups. These data suggest that Zenk-mediated processes of synaptic plasticity in the hippocampus are induced during the retrieval of conditioned fear memory in the pigeon.

Endogenous protection against the 6-OHDA model of Parkinson's disease in the Amazonian rodent Proechimys.

BACKGROUND: Proechimys, an epilepsy-resistant rodent from Amazon Rainforest, is a promising alternative animal model for studying neurodegenerative disorders. OBJECTIVES: To evaluate behavioral and immunohistological changes in Proechimys after 6-OHDA-induced model of PD. METHODS: Following unilateral injections of 6-OHDA into striatum, animals were assessed for exploratory behavior using the cylinder test. Brain sections were submitted to immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1). RESULTS: We observed normal exploratory behavior during cylinder test in all animals. We could not detect changes in the expression of TH in both striatum and SNc, suggesting that Proechimys is resistant to dopaminergic neuronal degeneration. Glial activation was observed by an increase in Iba-1 expression in both striatum and SNc, and by an increase in GFAP expression in striatum. CONCLUSIONS: Proechimys represents a promising animal model for studying the mechanisms underlying the susceptibility of dopaminergic neurons to degeneration induced by 6-OHDA.

Retinal alterations in a pre-clinical model of an autism spectrum disorder.

Background: Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes. Methods: Pregnant female mice received VPA (600 mg/kg, ip) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs). Results: Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal. Conclusions: This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.

Motor cortex and pain control: exploring the descending relay analgesic pathways and spinal nociceptive neurons in healthy conscious rats.

Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.