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1.
PLoS One ; 16(9): e0257960, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34591905

RESUMO

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.


Assuntos
Encéfalo/efeitos dos fármacos , Complemento C1q/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Via Clássica do Complemento/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/terapia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Terapia Combinada , Complemento C1q/metabolismo , Inativadores do Complemento/uso terapêutico , Modelos Animais de Doenças , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Resultado do Tratamento
2.
Biochem Biophys Res Commun ; 577: 38-44, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34507063

RESUMO

Sepsis is a life-threatening inflammatory syndrome secondary to infection. Thanks to the advances of antibiotics and life-supporting techniques, the mortality of sepsis has been decreasing in recent decades. Nevertheless, sepsis-associated encephalopathy (SAE) is still common in septic patients, which promotes the mortality of septic patients and results in cognitive dysfunction in survivors. Full understanding and effective medicine in the treatment of SAE is currently scant. Here, we revealed a novel role of cGAS signaling in the pathogenesis of SAE. Deficiency of cGas significantly restored cognitive impairment in sepsis mice model. The restoration may attribute to the recovery of neo-neuron decline that associated with the decrease of activated microglia and astrocytes in the hippocampus of cGas-deficient mice. In addition, type I interferon (IFN) signaling, a downstream of cGAS pathway, was boosted in the hippocampus of septic mice, which was dramatically attenuated by deleting cGas. Moreover, administration of recombinant IFNß markedly reversed the protection of ablation of cGas in the cognitive impairment in sepsis. Collectively, cGAS promotes the pathogenesis of SAE by up-regulating type I IFN signaling. Blocking cGAS may be a promising strategy for preventing encephalopathy in sepsis.


Assuntos
Modelos Animais de Doenças , Nucleotidiltransferases/genética , Encefalopatia Associada a Sepse/genética , Transdução de Sinais/genética , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interferon Tipo I/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurônios/metabolismo , Nucleotidiltransferases/deficiência , Substâncias Protetoras/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/fisiopatologia , Encefalopatia Associada a Sepse/metabolismo
3.
Biochem Biophys Res Commun ; 577: 52-57, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34507065

RESUMO

Focal ischemia causes irreversible brain damage if cerebral blood flow is not restored promptly. Acute phase excitotoxicity and pro-oxidant and inflammatory events in the sub-chronic phase elicit coagulative necrosis, vascular injury, cerebral oedema, and neurobehavioral deficits. Earlier, in pre-clinical studies arbutin protected behavioral functions and improved therapeutic outcomes in different models of brain and metabolic disorders. Arbutin is natural hydroquinone that might protect against ischemia-reperfusion (I/R) injury. In this study, cerebro-protective effects of arbutin were evaluated in the middle cerebral artery occlusion-reperfusion (MCAo/R) mouse model. Mice were administered arbutin (50, 100 mg/kg, i.p.) for 21 days, and subjected to MCAo/R or sham surgery on day 14. Results showed brain infarction, blood-brain barrier dysfunction, oedema, and neurological deficits 24 h post-MCAo/R injury that were prevented by arbutin. Behavioral evaluations over the sub-chronic phase revealed MCAo/R triggered spatial and working memory deficits. Arbutin protected the memory against MCAo/R injury and decreased hydroxy-2'-deoxyguanosine, protein carbonyls, inflammatory cytokines (tumor necrosis factor-α, myeloperoxidase, matrix metalloproteinase-9, inducible nitric oxide synthase), and enhanced glutathione levels in the ischemia ipsilateral hemisphere. Arbutin decreased brain acetylcholinesterase activity, glutamate, and enhanced GABA levels against MCAo/R. Arbutin can alleviate I/R pathogenesis and protects neurobehavioral functions in the MCAo/R mouse model.


Assuntos
Arbutina/farmacologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Encéfalo/fisiopatologia , Cromatografia Líquida de Alta Pressão , Ácido Glutâmico/metabolismo , Humanos , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Camundongos , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Permeabilidade/efeitos dos fármacos , Traumatismo por Reperfusão/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
4.
Clin Immunol ; 230: 108815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339843

RESUMO

Traumatic Brain Injury (TBI) is the most prevalent of all head injuries. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration. In this study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/etiologia , Microglia/fisiologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/psicologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Citometria de Fluxo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/classificação , Microglia/patologia , Modelos Neurológicos , Modelos Psicológicos , Dinâmica não Linear , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Análise Espaço-Temporal , Pesquisa Médica Translacional
5.
Biomolecules ; 11(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439857

RESUMO

Improvement of longevity is an eternal dream of human beings. The accumulation of protein damages is considered as a major cause of aging. Here, we report that the injection of exogenous recombinant mouse serum albumin (rMSA) reduced the total damages of serum albumin in C57BL/6N mice, with higher level of free-thiols, lower levels of carbonyls and advanced glycation end-products as well as homocysteines in rMSA-treated mice. The healthspan and lifespan of C57BL/6N mice were significantly improved by rMSA. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. Moreover, the median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no carbonylation, no advanced glycation end-product, and no homocysteinylation. Here, "young and undamaged" exogenous rMSA used in the present study is much younger and less damaged than the endogenous serum albumin purified from young mice at 1.5 months of age. We predict that undamaged proteins altogether can further improve the healthspan and lifespan of mice.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Longevidade/efeitos dos fármacos , Longevidade/fisiologia , Albumina Sérica/administração & dosagem , Fatores Etários , Animais , Feminino , Força da Mão/fisiologia , Injeções Intravenosas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem
6.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360003

RESUMO

Postsynaptic structures on excitatory neurons, dendritic spines, are actin-rich. It is well known that actin-binding proteins regulate actin dynamics and by this means orchestrate structural plasticity during the development of the brain, as well as synaptic plasticity mediating learning and memory processes. The actin-binding protein cortactin is localized to pre- and postsynaptic structures and translocates in a stimulus-dependent manner between spines and the dendritic compartment, thereby indicating a crucial role for synaptic plasticity and neuronal function. While it is known that cortactin directly binds F-actin, the Arp2/3 complex important for actin nucleation and branching as well as other factors involved in synaptic plasticity processes, its precise role in modulating actin remodeling in neurons needs to be deciphered. In this study, we characterized the general neuronal function of cortactin in knockout mice. Interestingly, we found that the loss of cortactin leads to deficits in hippocampus-dependent spatial memory formation. This impairment is correlated with a prominent dysregulation of functional and structural plasticity. Additional evidence shows impaired long-term potentiation in cortactin knockout mice together with a complete absence of structural spine plasticity. These phenotypes might at least in part be explained by alterations in the activity-dependent modulation of synaptic actin in cortactin-deficient neurons.


Assuntos
Citoesqueleto de Actina/genética , Actinas/genética , Cortactina/genética , Hipocampo/metabolismo , Memória Espacial/fisiologia , Coluna Vertebral/metabolismo , Citoesqueleto de Actina/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/metabolismo , Animais , Cortactina/deficiência , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtomia , Neurônios/metabolismo , Neurônios/patologia , Coluna Vertebral/fisiopatologia , Transmissão Sináptica , Técnicas de Cultura de Tecidos
7.
Biochem Biophys Res Commun ; 569: 35-40, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34225078

RESUMO

Recently, coagulation factor IX and its activation peptide have been reported to suppress the permeability of vascular endothelial cells. In this study, the therapeutic effects of a synthesized activation peptide is investigated in traumatic brain injury model rats. In cerebral contusion, dysfunction of the blood brain barrier with increasing vascular permeability promotes the progression of neuropathy after injury. The model rats were generated by controlled cortical impact. Then, rats were intravenously injected with 350 µg/kg of the synthesized activation peptide or PBS as a control, every day for a month. Behavioral studies were conducted during a month of observation. For morphological analysis, macro- and microscopic observation were performed. Water content of brain tissue was used to assess edema. To assess the function of blood brain barrier, Evans Blue method was employed. In the neurological examinations and beam-walking, the treated rats performed significantly better than control rats. Measurements of cerebral defect volume showed that the treatment significantly reduced it by 82%. Nissl stain showed that neural cells adjacent to impacts were lost in control rats, but saved in treated rats. The treatment significantly reduced brain edema and extravascular leakage of Evans blue. Intravenous injection with a synthesized activation peptide significantly reduced damage to neural tissue and improved neural functioning in the model rats.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/prevenção & controle , Fator IX/química , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Comportamento Animal/fisiologia , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Lesões Encefálicas Traumáticas/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Peptídeos/administração & dosagem , Peptídeos/química , Prognóstico , Ratos Endogâmicos WKY , Resultado do Tratamento
8.
Biochem Biophys Res Commun ; 569: 54-60, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34229123

RESUMO

Cholinergic crisis and oxidative stress in the hippocampus of the brain have been known to induce anxiety disorders upon ageing. BOTOX® is a widely used therapeutic form of botulinum neurotoxin that acts by inhibiting the release of acetylcholine (ACh) from the nerve terminals at the neuromuscular junction. BOTOX® can migrate from the muscle to the brain through retrograde axonal transport and modulate neuroplasticity. While a mild dose of BOTOX® has been used to manage various neurological deficits and psychiatric complications including depression, the efficacy and experimental evidence for its anxiolytic effects and antioxidant properties remain limited. In this study, we have investigated the effect of BOTOX® on the innate anxiety-like behaviours in ageing mice upon exposure to different behavioural paradigms like open field test, elevated plus maze and light-dark box test, and estimated the enzymatic activities of key antioxidants in the hippocampus. Results revealed that animals injected with a mild intramuscular dosage of BOTOX® showed reduced level of innate anxiety-related symptoms and increased activities of hippocampal antioxidant enzymes compared to the control group. This study strongly supports that BOTOX® could be implemented to prevent or treat anxiety and hippocampal oxidative stress resulting from ageing, emotional and mood disorders.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/metabolismo , Ansiedade/prevenção & controle , Toxinas Botulínicas Tipo A/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hipocampo/enzimologia , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/farmacologia , Superóxido Dismutase/metabolismo
9.
J Neurosci ; 41(33): 6987-7002, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34266900

RESUMO

Activity-dependent insertion of the tropomyosin-related kinase B (TrkB) receptor into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons and synapses; however, the underlying molecular mechanisms remain obscure. Here, we report a novel function for carboxypeptidase E (CPE) in controlling chemical long-term potentiation stimuli-induced TrkB surface delivery in hippocampal neurons. Total internal reflection fluorescence assays and line plot assays showed that CPE facilitates TrkB transport from dendritic shafts to the plasma membrane. The Box2 domain in the juxtamembrane region of TrkB and the C terminus of CPE are critical for the activity-dependent plasma membrane insertion of TrkB. Moreover, the transactivator of transcription TAT-CPE452-466, which could block the association between CPE and TrkB, significantly inhibited neuronal activity-enhanced BDNF signaling and dendritic spine morphologic plasticity in cultured hippocampal neurons. Microinfusion of TAT-CPE452-466 into the dorsal hippocampus of male C57BL/6 mice inhibited the endogenous interaction between TrkB and CPE and diminished fear-conditioning-induced TrkB phosphorylation, which might lead to an impairment in hippocampal memory acquisition and consolidation but not retrieval. These results suggest that CPE modulates activity-induced TrkB surface insertion and hippocampal-dependent memory and sheds light on our understanding of the role of CPE in TrkB-dependent synaptic plasticity and memory modulation.SIGNIFICANCE STATEMENT It is well known that BDNF acts preferentially on active neurons; however, the underlying molecular mechanism is not fully understood. In this study, we found that the cytoplasmic tail of CPE could interact with TrkB and facilitate the neuronal activity-dependent movement of TrkB vesicles to the plasma membrane. Blocking the association between CPE and TrkB decreased fear-conditioning-induced TrkB phosphorylation and led to hippocampal memory deficits. These findings provide novel insights into the role of CPE in TrkB intracellular trafficking as well as in mediating BDNF/TrkB function in synaptic plasticity and hippocampal memory.


Assuntos
Aprendizagem da Esquiva/fisiologia , Carboxipeptidase H/fisiologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neurônios/enzimologia , Proteínas Tirosina Quinases/metabolismo , Reconhecimento Psicológico/fisiologia , Animais , Biotinilação , Medo/fisiologia , Células HEK293 , Humanos , Microscopia Intravital , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/ultraestrutura , Teste de Campo Aberto , Transporte Proteico , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Transdução de Sinais
10.
Elife ; 102021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196271

RESUMO

Animals learn certain complex tasks remarkably fast, sometimes after a single experience. What behavioral algorithms support this efficiency? Many contemporary studies based on two-alternative-forced-choice (2AFC) tasks observe only slow or incomplete learning. As an alternative, we study the unconstrained behavior of mice in a complex labyrinth and measure the dynamics of learning and the behaviors that enable it. A mouse in the labyrinth makes ~2000 navigation decisions per hour. The animal explores the maze, quickly discovers the location of a reward, and executes correct 10-bit choices after only 10 reward experiences - a learning rate 1000-fold higher than in 2AFC experiments. Many mice improve discontinuously from one minute to the next, suggesting moments of sudden insight about the structure of the labyrinth. The underlying search algorithm does not require a global memory of places visited and is largely explained by purely local turning rules.


Assuntos
Comportamento Exploratório/fisiologia , Aprendizagem em Labirinto/fisiologia , Algoritmos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravação em Vídeo
11.
Neuron ; 109(14): 2292-2307.e5, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34102111

RESUMO

Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Aprendizagem em Labirinto/fisiologia , Bainha de Mielina/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo
12.
J Alzheimers Dis ; 82(3): 1183-1202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34151790

RESUMO

BACKGROUND: The use of Alzheimer's disease (AD) models obtained by intracerebral infusion of amyloid-ß (Aß) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. OBJECTIVE: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-ß42 (Aß42). METHODS: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aß42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aß42 injection. Aß deposition, tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aß42 administration. RESULTS: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aß42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aß icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. CONCLUSION: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aß injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Modelos Animais de Doenças , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Fragmentos de Peptídeos/toxicidade , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/administração & dosagem , Animais , Hipocampo/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Ratos , Ratos Wistar
13.
J Neurochem ; 158(3): 779-797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107061

RESUMO

Clinical diagnosis of Parkinson's disease (PD) occurs typically when a substantial proportion of dopaminergic neurons in the substantia nigra (SN) already died, and the first motor symptoms appear. Therefore, tools enabling the early diagnosis of PD are essential to identify early-stage PD patients in which neuroprotective treatments could have a significant impact. Here, we test the utility and sensitivity of the diffusion kurtosis imaging (DKI) in detecting progressive microstructural changes in several brain regions of mice exposed to chronic intragastric administration of rotenone, a mouse model that mimics the spatiotemporal progression of PD-like pathology from the ENS to the SN as described by Braak's staging. Our results show that DKI, especially kurtosis, can detect the progression of pathology-associated changes throughout the CNS. Increases in mean kurtosis were first observed in the dorsal motor nucleus of the vagus (DMV) after 2 months of exposure to rotenone and before the loss of dopaminergic neurons in the SN occurred. Remarkably, we also show that limited exposure to rotenone for 2 months is enough to trigger the progression of the disease in the absence of the environmental toxin, thus suggesting that once the first pathological changes in one region appear, they can self-perpetuate and progress within the CNS. Overall, our results show that DKI can be a useful radiological marker for the early detection and monitoring of PD pathology progression in patients with the potential to improve the clinical diagnosis and the development of neuroprotective treatments.


Assuntos
Imagem de Tensor de Difusão/métodos , Progressão da Doença , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Rotenona/toxicidade , Administração Oral , Animais , Inseticidas/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Rotenona/administração & dosagem , Fatores de Tempo
14.
Psychopharmacology (Berl) ; 238(8): 2297-2312, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33991198

RESUMO

RATIONALE AND OBJECTIVE: Environmental enrichment (EE) has been shown in old rats to improve learning and memory. Vitamin D (VitD) has also been shown to modulate age-related, cognitive dysfunction. As both EE and VitD could work to improve cognition via enhancement of neurotrophic factors, their effects might occlude one another. Therefore, a clinically relevant question is whether noted cognition-promoting effects of EE and VitD can co-occur. METHODS: Aged rats were housed for 6 weeks in one of three housing conditions: environmentally enriched (EE), socially enriched (SE), or standard condition (SC). Further, a 4th group was co-treated with VitD supplementation (400 IU kg-1 daily, 6 weeks) under EE conditions (EE + VitD). RESULTS: Treatment with VitD and EE housing were associated with higher score on measures of learning and memory and exhibited lower anxiety scores compared to EE alone, SE or SC as assayed in the elevated plus maze, Morris water maze, passive avoidance, and open field tasks. Additionally, in the EE + VitD group, mRNA expression levels of NGF, TrkA, BDNF, Nrf2, and IGF-1 were significantly higher compared to expression seen in the EE group. Furthermore, field potential recordings showed that EE + VitD resulted in a greater enhancement of hippocampal LTP and neuronal excitability when compared to EE alone. CONCLUSIONS: These findings demonstrate that in aged rats exposure to EE and VitD results in effects on hippocampal cognitive dysfunction and molecular mechanisms which are greater than effects of EE alone, suggesting potential for synergistic therapeutic effects for management of age-related cognitive decline.


Assuntos
Envelhecimento/fisiologia , Meio Ambiente , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem Espacial/fisiologia , Vitamina D/administração & dosagem , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Suplementos Nutricionais , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos
15.
Nat Commun ; 12(1): 2695, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976205

RESUMO

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.


Assuntos
Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neurônios/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Células Cultivadas , Células HEK293 , Humanos , Imunossupressores/farmacologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia
16.
J Alzheimers Dis ; 81(4): 1403-1418, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935099

RESUMO

BACKGROUND: Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. OBJECTIVE: To study the potential toxic role of tau T217-phosphorylation. METHODS: We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. RESULTS: We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. CONCLUSION: T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.


Assuntos
Cognição/fisiologia , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Disfunção Cognitiva/patologia , Hipocampo/patologia , Humanos , Camundongos , Fosforilação , Tauopatias/patologia
17.
ScientificWorldJournal ; 2021: 6649574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994883

RESUMO

Garugapinnata Roxb. (Burseraceae) is a medium-sized tree widely available all over the tropical regions of Asia. Bryophyllum pinnatum (Lam) Oken. (Crassulaceae) is an indigenous and exotic plant grown in tropical regions. Both plants have been used for their anti-inflammatory, antioxidant, anticancer, wound healing, antidiabetic activities, etc. This investigation was designed to explore the result shown by methanolic extract of Garuga pinnata bark and Bryophyllum pinnatum leaves, on cognitive power and retention of the memory in experimental mice along with quantification of phenolic compounds and DPPH radicals neutralizing capacity. The memory-enhancing activity was determined by the elevated plus-maze method in Scopolamine-induced amnesic mice, using Piracetam as allopathic and Shankhpushpi as ayurvedic standard drugs. Two doses (200 and 400 mg/kg p.o.) of both extracts were administered to mice up to 8 consecutive days; transfer latency of individual group was recorded after 45 minutes and memory of the experienced things was examined after 1 day. DPPH assay method and the Folin-Ciocalteu method were employed to determine antioxidant potency and total phenol amount, respectively. 400 mg/kg of the methanolic B. pinnatum bark extract significantly improved memory and learning of mice with transfer latency (TL) of 32.75 s, which is comparable to that of standard Piracetam (21.78 s) and Shankhpushpi (27.83 s). Greater phenolic content was quantified in B. pinnatum bark extract (156.80 ± 0.33 µg GAE/mg dry extract) as well as the antioxidant potency (69.77% of free radical inhibition at the 100 µg/mL concentration). Our study proclaimed the scientific evidence for the memory-boosting effect of both plants.


Assuntos
Amnésia/tratamento farmacológico , Antioxidantes/farmacologia , Burseraceae/química , Kalanchoe/química , Nootrópicos/farmacologia , Compostos Fitoquímicos/farmacologia , Amnésia/induzido quimicamente , Amnésia/fisiopatologia , Animais , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Cognição/efeitos dos fármacos , Cognição/fisiologia , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Nootrópicos/isolamento & purificação , Fenóis/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Picratos/antagonistas & inibidores , Piracetam/farmacologia , Casca de Planta/química , Extratos Vegetais/química , Folhas de Planta/química , Preparações de Plantas/farmacologia , Escopolamina/administração & dosagem
18.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802338

RESUMO

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiologia , Neurotransmissores/metabolismo , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/fisiopatologia , Animais , Animais Recém-Nascidos/metabolismo , Animais Recém-Nascidos/fisiologia , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Depressão/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Masculino , Privação Materna , Aprendizagem em Labirinto/fisiologia , Imagem Molecular/métodos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Natação/fisiologia
19.
Exp Neurol ; 341: 113714, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33831399

RESUMO

The CDC estimate that nearly 3 million Americans sustain a traumatic brain injury (TBI) each year. Even when medical comorbidities are accounted for, age is an independent risk factor for poor outcome after TBI. Nonetheless, few studies have examined the pathophysiology of age-linked biologic outcomes in TBI. We hypothesized that aged mice would demonstrate more severe neuropathology and greater functional deficits as compared to young adult mice after equivalent traumatic brain injuries. Young adult (14-week-old) and aged (80-week-old) C57BL/6 male mice underwent an open-head controlled cortical impact to induce TBI or a sham injury. At 30-days post-injury groups underwent behavioral phenotyping, magnetic resonance imaging, and histologic analyses. Contrary to our hypothesis, young adult TBI mice exhibited more severe neuropathology and greater loss of white matter connectivity as compared to aged mice after TBI. These findings correlated to differential functional outcomes in anxiety response, learning, and memory between young adult and aged mice after TBI. Although the mechanisms underlying this age-effect remain unclear, attenuated signs of secondary brain injury in aged TBI mice point towards different inflammatory and repair processes between age groups. These data suggest that age may need to be an a priori consideration in future clinical trial design.


Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Recuperação de Função Fisiológica/fisiologia , Animais , Imageamento por Ressonância Magnética/métodos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento
20.
Exp Neurol ; 341: 113721, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33852877

RESUMO

Traumatic brain injury (TBI) is often associated with sustained attention and memory deficits. As persisting neuroinflammation and neurodegeneration may contribute to posttraumatic psychomotor dysfunction, we studied the relationship of brain cellular reactions three months after a weight-drop closed head injury in male mice with posttraumatic learning and memory using automated home-cage monitoring of socially housed mice in IntelliCages as well as tests for locomotor activity, anxiety and forepaw fine motor skills. One month after TBI, deficits in place learning and cognitive flexibility in reverse learning were clearly detectable in IntelliCages and these memory deficits correlated with the initial trauma severity on the functional neuroscore. While sucrose preference or its extinction were not influenced by TBI, traumatized mice performed significantly worse in a complex episodic memory learning task. In consecutive locomotor and forepaw skilled use tests, posttraumatic hyperactivity and impairment of contralateral paw use were evident. Analysis of cellular reactions to TBI three months after injury in selected defined regions of interest in the immediate lesion, ipsi- and contralateral frontoparietal cortex and hippocampus revealed a persistent microgliosis and astrogliosis which were accompanied by iron-containing macrophages and myelin degradation in the lesion area as well as with axonal damage in the neighboring cortical regions. Microglial and astroglial reactions in cortex showed a positive correlation with the initial trauma severity and a negative correlation with the spatial and episodic memory indicating a role of brain inflammatory reactions in posttraumatic memory deficits.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Gliose/patologia , Gliose/fisiopatologia , Índice de Gravidade de Doença , Aprendizagem Espacial/fisiologia , Animais , Lesões Encefálicas Traumáticas/complicações , Gliose/etiologia , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
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