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1.
PLoS One ; 15(6): e0234930, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559228

RESUMO

Synaptic plasticity is the cellular basis of learning and memory. When animals learn a novel motor skill, synaptic modifications are induced in the primary motor cortex (M1), and new postsynaptic dendritic spines relevant to motor memory are formed in the early stage of learning. However, it is poorly understood how presynaptic axonal boutons are formed, eliminated, and maintained during motor learning, and whether long-range corticocortical and thalamocortical axonal boutons show distinct structural changes during learning. In this study, we conducted two-photon imaging of presynaptic boutons of long-range axons in layer 1 (L1) of the mouse M1 during the 7-day learning of an accelerating rotarod task. The training-period-averaged rate of formation of boutons on axons projecting from the secondary motor cortical area increased, while the average rate of elimination of those from the motor thalamus (thalamic boutons) decreased. In particular, the elimination rate of thalamic boutons during days 4-7 was lower than that in untrained mice, and the fraction of pre-existing thalamic boutons that survived until day 7 was higher than that in untrained mice. Our results suggest that the late stabilization of thalamic boutons in M1 contributes to motor skill learning.


Assuntos
Córtex Cerebral/fisiologia , Aprendizagem , Movimento , Terminações Pré-Sinápticas/fisiologia , Tálamo/fisiologia , Animais , Córtex Cerebral/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Teste de Desempenho do Rota-Rod , Tálamo/citologia
2.
Life Sci ; 253: 117745, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376269

RESUMO

AIMS: Neuroinflammation and apoptosis play a crucial role in Parkinson's disease (PD) pathogenesis. Eupatilin is a lipophilic flavonoid isolated from Artemisia species and exerts anti-apoptotic and anti-inflammatory activities. In this study, we investigated the effects of Eupatilin on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAIN METHODS: The rotarod test and traction test were constructed to examine the motor function. Immunofluorescent staining was performed to detect the expression of TH, Iba-1 and GFAP. Apoptosis was examined by the TUNEL assay. Real-time PCR was used to determine the mRNA expression and Western blot and ELISA were used to determine the protein expression. KEY FINDINGS: Eupatilin improved behavioral impairment caused by MPTP. A loss of TH positive neurons was observed in the substantia nigra pars compacta of MPTP-lesioned brain, while it was rescued by Eupatilin. Moreover, MPTP administration increased the cell number of microglia and astrocytes and the expression of inflammatory factors TNF-α, IL-1ß, and IL-6. Whereas Eupatilin suppressed the activation of neuroinflammation. Eupatilin also decreased cell apoptosis enhanced by MPTP/MPP+ exposure in vivo and in vitro. We further revealed that Eupatilin abolished MPTP-induced downregulation of IκBα expression and accumulation of p65 in the nuclear compartment. Besides, MPTP administration led to dephosphorylation of Akt and GSK-3ß, but it was restored by Eupatilin. SIGNIFICANCE: We demonstrate that Eupatilin alleviates behavioral impairment and dopaminergic neuron loss induced by MPTP through inhibition of neuroinflammation and apoptosis. Our research provides more evidence for Eupatilin as a potential preventative drug for PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Flavonoides/farmacologia , Degeneração Neural/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/patologia , Teste de Desempenho do Rota-Rod
3.
J Surg Res ; 251: 311-320, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32200322

RESUMO

BACKGROUND: Outcome assessments that evaluate post-transection nerve repair do not often correlate with one another. The aims of this study were twofold: to compare four nerve repair techniques with each other and incorporate both negative and positive control groups and to identify possible correlations between outcome assessments. MATERIALS AND METHODS: Sciatic nerve transection and repair was performed in Lewis rats using one of the following techniques: interrupted epineural, running epineural, grouped fascicular, epineural with absorbable type I collagen wrap, and high tension for incorporation of a negative control. A sham surgery group was also included as a positive control group. Outcomes were compared using assessments of functional recovery (behavior and electrophysiology) and nerve regrowth (imaging and histomorphometry). Three-dimensional printed custom electrode stabilization and imaging devices were designed and fabricated to provide standardization in assessment between subjects. RESULTS: Nerve repair was performed in 48 male Lewis rats. In all animals, functional testing was performed at week 13. The sham group (n = 7) performed the best on both behavioral assays (P < 0.001) and electrophysiology assessments (P < 0.001). The negative control group (high tension) performed poorest on multiple assessments, and there were no significant differences observed for any of the four repair types. Positive correlations were observed between behavioral and histomorphometric tests. CONCLUSIONS: There was no difference in outcome between the four types of nerve repair. High-tension nerve repair represents an ideal negative control. Not all assessment methods correlate equally, and consistent use of complimentary outcome assessments could allow for improved comparison between studies.


Assuntos
Regeneração Nervosa , Procedimentos Neurocirúrgicos/métodos , Nervo Isquiático/lesões , Animais , Masculino , Procedimentos Neurocirúrgicos/reabilitação , Ratos Endogâmicos Lew , Teste de Desempenho do Rota-Rod , Nervo Isquiático/fisiologia
4.
BMC Complement Med Ther ; 20(1): 20, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-32020857

RESUMO

BACKGROUND: Danshensu is an active constituent in the extracts of Danshen which is a traditional Chinese medical herb. Rotenone inhibits complex I of the mitochondrial electron transport chain in dopaminergic neurons leading to glutathione (GSH) level reduction and oxidative stress. The aim of this study is to investigate neuroprotective effects of Danshensu on rotenone-induced Parkinson's disease (PD) in vitro and in vivo. METHODS: In vitro, SH-SY5Y human neuroblastoma cell line was pretreated with Danshensu and challenged with rotenone. Then the reactive oxygen species (ROS) production was assayed. In vivo, male C57BL/6 mice were intragastrically administered with Danshensu (15, 30, or 60 mg/kg), followed by oral administration with rotenone at a dose of 30 mg/kg. Pole and rotarod tests were carried out at 28 d to observe the effects of Danshensu on PD. RESULTS: Danshensu repressed ROS generation and therefore attenuated the rotenone-induced injury in SH-SY5Y cells. Danshensu improved motor dysfunction induced by rotenone, accompanied with reducing MDA content and increasing GSH level in striatum. Danshensu increased the number of TH positive neurons, the expression of TH and the dopamine contents. The expressions of p-PI3K, p-AKT, Nrf2, hemeoxygenase (HO-1), glutathione cysteine ligase regulatory subunit (GCLC), glutathione cysteine ligase modulatory subunit (GCLM) were significantly increased and the expression of Keap1 was decreased in Danshensu groups. CONCLUSIONS: The neuroprotective effects of Danshensu on rotenone-induced PD are attributed to the anti-oxidative properties by activating PI3K/AKT/Nrf2 pathway and increasing Nrf2-induced expression of HO-1, GCLC, and GCLM, at least in part.


Assuntos
Lactatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Western Blotting , Linhagem Celular Tumoral , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Teste de Desempenho do Rota-Rod , Rotenona
5.
Ann Neurol ; 87(3): 480-485, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31925837

RESUMO

Marked elevation in the brain concentration of N-acetyl-L-aspartate (NAA) is a characteristic feature of Canavan disease, a vacuolar leukodystrophy resulting from deficiency of the oligodendroglial NAA-cleaving enzyme aspartoacylase. We now demonstrate that inhibiting NAA synthesis by intracisternal administration of a locked nucleic acid antisense oligonucleotide to young-adult aspartoacylase-deficient mice reverses their pre-existing ataxia and diminishes cerebellar and thalamic vacuolation and Purkinje cell dendritic atrophy. Ann Neurol 2020;87:480-485.


Assuntos
Ácido Aspártico/análogos & derivados , Doença de Canavan/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Acetiltransferases/antagonistas & inibidores , Amidoidrolases/deficiência , Amidoidrolases/genética , Animais , Ácido Aspártico/biossíntese , Ataxia/complicações , Ataxia/tratamento farmacológico , Atrofia/complicações , Atrofia/tratamento farmacológico , Doença de Canavan/complicações , Doença de Canavan/patologia , Cerebelo/patologia , Feminino , Técnicas de Silenciamento de Genes , Infusões Intraventriculares , Masculino , Camundongos , Mutação , Oligonucleotídeos Antissenso/administração & dosagem , Células de Purkinje/patologia , Teste de Desempenho do Rota-Rod , Tálamo/patologia , Vacúolos/efeitos dos fármacos , Vacúolos/patologia
6.
J Neurosci ; 40(7): 1483-1500, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31911460

RESUMO

Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knock-out of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knock-out in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knock-out mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.SIGNIFICANCE STATEMENT Replacement of oligodendroglia and myelin regeneration holds tremendous potential to improve function across neurological conditions. Here we demonstrate Protease Activated Receptor 1 (PAR1) is an important regulator of the capacity for myelin regeneration across two experimental murine models of myelin injury. PAR1 is a G-protein-coupled receptor densely expressed in the CNS, however there is limited information regarding its physiological roles in health and disease. Using a combination of PAR1 knock-out mice, oligodendrocyte monocultures and oligodendrocyte-astrocyte cocultures, we demonstrate blocking PAR1 improves myelin production by a mechanism related to effects across glial compartments and linked in part to regulatory actions toward growth factors such as BDNF. These findings set the stage for development of new clinically relevant myelin regeneration strategies.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Regeneração Nervosa/efeitos dos fármacos , Receptor PAR-1/antagonistas & inibidores , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Quelantes/toxicidade , Técnicas de Cocultura , Cobre , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Perfilação da Expressão Gênica , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Knockout , Bainha de Mielina/fisiologia , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Receptor PAR-1/deficiência , Receptor PAR-1/fisiologia , Teste de Desempenho do Rota-Rod , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
7.
PLoS One ; 15(1): e0227624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945776

RESUMO

Limb remote ischemic postconditioning (LRIP) has been reported as an effective method to reduce the induced experimental stroke damage after ischemic reperfusion (IR) injury. Studies suggest that anesthetics used during induction of ischemic stroke can reduce IR injury, which could affect the actual mechanisms of neuroprotection by LRIP. This study focuses on the comparative effects of anesthetics such as isoflurane and ketamine-xylazine on ischemic injury when used during LRIP. Adult C57BL/6 mice were anesthetized by isoflurane or halothane, and transient middle cerebral artery occlusion (MCAO) was induced through insertion of the filament. Under isoflurane or ketamine-xylazine anesthesia, LRIP was performed after 90 min of reperfusion by carrying out three cycles of 5 min ischemia/5 min reperfusion of the bilateral hind limbs for one session per day for a total of 3 days. Results showed that the use of different anesthetics-isoflurane or ketamine-xylazine-during LRIP had no effects on body weight. However, LRIP was able to improve neurological function as observed by the neurological deficit score in ischemic mice. Interestingly, the neurological deficit in the group where ketamine-xylazine was used was better than the group where isoflurane was used during LRIP. Furthermore, the LRIP was able to prolong the period of the ischemic mice on the rotarod and this effect was more significant in the groups where ketamine-xylazine was used during LRIP. Moreover, LRIP significantly attenuated the infarction volume; however, this effect was independent of the anesthetic used during LRIP. From these results, we conclude that ischemic mice that were subjected to LRIP under ketamine-xylazine anesthesia had better neurological deficit outcomes after stroke.


Assuntos
Anestésicos/farmacologia , Infarto Encefálico/tratamento farmacológico , Extremidades/irrigação sanguínea , Pós-Condicionamento Isquêmico/métodos , Acidente Vascular Cerebral/terapia , Analgésicos/farmacologia , Animais , Infarto Encefálico/patologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/terapia , Halotano/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Isoflurano/farmacologia , Ketamina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/prevenção & controle , Teste de Desempenho do Rota-Rod , Acidente Vascular Cerebral/etiologia , Xilazina/farmacologia
8.
Food Chem Toxicol ; 135: 111043, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31836553

RESUMO

Tylorrhynchus heterochaetus (Hechong in Chinese) has been used in Chinese traditional medicine for treating various diseases. This study was aimed to assess the anti-fatigue effect of T. heterochaetus on Kunming mice and its primary mechanism of action using forced running, rotating rod and weight-loaded swimming tests. Low (2.70 mg/0.5 mL/20 g), medium (5.41 mg/0.5 mL/20 g) and high (6.58 mg/0.5 mL/20 g) doses of T. heterochaetus aqueous extract were treated to mice for 28 days. Among the doses, the low and medium doses showed significant (p ≤ 0.05) anti-fatigue effect on the weight-loaded swimming test. Also, T. heterochaetus extract showed significant (p ≤ 0.05) effects on fatigue-related blood parameters by increasing the GLU, TG and LDH levels and decreasing the LA, CK and BUN levels. The levels of liver and skeletal muscle glycogen were also significantly (p ≤ 0.05) increased after treatment. Further, on Western blot analysis, it has been found that T. heterochaetus enhanced the expressions of AMPK and PGC-1α in the liver and skeletal muscles of mice. From the study, our outcomes suggest that T. heterochaetus possess an anti-fatigue effect through the AMPK-linked pathway and thereby it can regularize the energy metabolism.


Assuntos
Adenilato Quinase/metabolismo , Produtos Biológicos/farmacologia , Fadiga/prevenção & controle , Poliquetos/química , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Creatina Quinase/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Teste de Desempenho do Rota-Rod , Corrida , Natação , Triglicerídeos/metabolismo
9.
Food Chem Toxicol ; 135: 111053, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31857126

RESUMO

Chronic pain management has several adverse effects and research looking for new and effective pain management drugs posing lower undesirable effects is necessary. Given the above, the pharmacological investigation of medicinal plants significantly contributes to the dissemination of plant-derived therapeutics. The aim of this study was to evaluate the antinociceptive activity of the Psidium brownianum Mart ex DC. leaf essential oil (PBEO) and the participation of the opioid pathway in this effect in mice. Swiss Mus musculus male mice were tested using acute nociception models (acetic acid induced abdominal contortions, formalin, capsaicin and hot plate tests). The possible myorelaxant action of the PBEO was tested using the rotarod test. The essential oil reduced animal nociception in chemical and heat models, with this action being devoid of a myorelaxant effect. Naloxone (2 mg/kg, intraperitoneally - i.p.) partially antagonized the PBEO activity, possibly acting via opioid receptors. The results obtained provide evidence that the traditional Psidium brownianum use may be effective for pain treatment.


Assuntos
Analgésicos/farmacologia , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Psidium/química , Animais , Modelos Animais de Doenças , Dose Letal Mediana , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Teste de Desempenho do Rota-Rod
10.
Ann Ist Super Sanita ; 55(4): 330-337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31850859

RESUMO

BACKGROUND: Physical exercise can reduce the risk of developing chronic diseases and slow the onset of neurodegenerative diseases. Since it has not been assessed which kind of training protocol might positively modulate both synaptic and muscular plasticity in neurodegenerative diseases, we studied in a mouse model of Niemann Pick type C disease, a model of minimal Alzheimer's Disease, the effect of a short term protocol. METHODS: We evaluated the effect of a short term, aerobic uniform exercise training on synaptic and muscle plasticity in three different mice groups: WT controls, NPC1+/- and NPC1-/- animals. The results were compared with those obtained in the sedentary respective groups. We analyzed the effects on synaptic plasticity by in vitro extracellular recordings in hippocampal mouse slices; moreover hippocampal and muscle tissue morphological structure have been investigated by transmission electron microscopy, to highlight any structural and functional changes due to training. RESULTS: The results indicate a rescue of long-term potentiation in homozygous but not in heterozygous mice slices and an induction of neuronal plasticity, observed by morphological analysis, both in homozygous and in heterozygous trained mice. CONCLUSIONS: Hence this protocol is adequate to improve long term potentiation (LTP) impairment and counteract muscular deterioration in homozygous mice.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Potenciação de Longa Duração , Atrofia Muscular/prevenção & controle , Doença de Niemann-Pick Tipo C/terapia , Condicionamento Físico Animal , Sarcômeros/ultraestrutura , Aerobiose , Animais , Região CA1 Hipocampal/fisiopatologia , Genótipo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/fisiopatologia , Teste de Desempenho do Rota-Rod
11.
J Neuroinflammation ; 16(1): 218, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727149

RESUMO

BACKGROUND: The development of new therapeutic strategies to treat amyotrophic lateral sclerosis (ALS) is of utmost importance. The use of cyclic nitroxides such as tempol may provide neuroprotection and improve lifespan. We investigated whether tempol (50 mg/kg) presents therapeutic potential in SOD1G93A transgenic mice. METHODS: Tempol treatment began at the asymptomatic phase of the disease (10th week) and was administered every other day until week 14, after which it was administered twice a week until the final stage of the disease. The animals were sacrificed at week 14 (initial stage of symptoms-ISS) and at the end stage (ES) of the disease. The lumbar spinal cord of the animals was dissected and processed for use in the following techniques: Nissl staining to evaluate neuronal survival; immunohistochemistry to evaluate astrogliosis and microgliosis (ISS and ES); qRT-PCR to evaluate the expression of neurotrophic factors and pro-inflammatory cytokines (ISS); and transmission electron microscopy to evaluate the alpha-motoneurons (ES). Behavioral analyses considering the survival of animals, bodyweight loss, and Rotarod motor performance test started on week 10 and were performed every 3 days until the end-stage of the disease. RESULTS: The results revealed that treatment with tempol promoted greater neuronal survival (23%) at ISS compared to untreated animals, which was maintained until ES. The intense reactivity of astrocytes and microglia observed in vehicle animals was reduced in the lumbar spinal cords of the animals treated with tempol. In addition, the groups treated with tempol showed reduced expression of proinflammatory cytokines (IL1ß and TNFα) and a three-fold decrease in the expression of TGFß1 at ISS compared with the group treated with vehicle. CONCLUSIONS: Altogether, our results indicate that treatment with tempol has beneficial effects, delaying the onset of the disease by enhancing neuronal survival and decreasing glial cell reactivity during ALS progression in SOD1G93A mice.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Óxidos N-Cíclicos/uso terapêutico , Inflamação/tratamento farmacológico , Destreza Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Medula Espinal/efeitos dos fármacos , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Destreza Motora/fisiologia , Fármacos Neuroprotetores/farmacologia , Teste de Desempenho do Rota-Rod , Marcadores de Spin , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
PLoS One ; 14(10): e0223820, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603928

RESUMO

Currently, many ischemic stroke patients worldwide suffer from physical and mental impairments, and thus have a low quality of life. However, although rehabilitation is acknowledged as an effective way to recover patients' health, there does not exist yet an adaptive training platform for animal tests so far. For this sake, this paper aims to develop an adaptive escalator (AE) for rehabilitation of rats with cerebral ischemia. Rats were observed to climb upward spontaneously, and a motor-driven escalator, equipped with a position detection feature and an acceleration/deceleration mechanism, was constructed accordingly as an adaptive training platform. The rehabilitation performance was subsequently rated using an incline test, a rotarod test, the infarction volume, the lesion volume, the number of MAP2 positive cells and the level of cortisol. This paper is presented in 3 parts as follows. Part 1 refers to the escalator mechanism design, part 2 describes the adaptive ladder-climbing rehabilitation mechanism, and part 3 discusses the validation of an ischemic stroke model. As it turned out, a rehabilitated group using this training platform, designated as the AE group, significantly outperformed a control counterpart in terms of a rotarod test. After the sacrifice of the rats, the AE group gave an average infarction volume of (34.36 ± 3.8)%, while the control group gave (66.41 ± 3.1)%, validating the outperformance of the escalator-based rehabilitation platform in a sense. An obvious difference between the presented training platform and conventional counterparts is the platform mechanism, and for the first time in the literature rats can be well and voluntarily rehabilitated at full capacity using an adaptive escalator. Taking into account the physical diversity among rats, the training strength provided was made adaptive as a reliable way to eliminate workout or secondary injury. Accordingly, more convincing arguments can be made using this mental stress-free training platform.


Assuntos
Isquemia Encefálica/reabilitação , Infarto Cerebral/reabilitação , Reabilitação do Acidente Vascular Cerebral/instrumentação , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/fisiopatologia , Infarto Cerebral/etiologia , Infarto Cerebral/fisiopatologia , Modelos Animais de Doenças , Elevadores e Escadas Rolantes , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Teste de Desempenho do Rota-Rod
13.
Biol Pharm Bull ; 42(11): 1867-1876, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484847

RESUMO

Anandamide (AEA) played potent neuroprotective activities via cannabinoid type 1 (CB1) and 2 (CB2) receptor. N-Linoleyltyrosine (NITyr), as an AEA analogue, was synthesized in our laboratory and evaluated the neuroprotective effects and mechanisms for the first time. NITyr was synthesized via substitution reaction. The neuroprotective effects of NITyr were evaluated in a gerbil model of transient cerebral ischemia. Each gerbil was subjected to open field test (OFT), Rotard rod test (RRT), Morris water maze (MWM) successively and executed after animal behaviors. Part of the brain was stained with hematoxylin and eosin (HE) and Nissl staining, and the rest for biochemical analysis. NITyr could not increase spontaneous locomotor activity and ameliorate the anxiety behavior in the OFT but could improve the motor coordination in the RRT and the spatial memory impairment in the MWM. Immunohistochemically, NITyr could attenuate the ischemia-induced neural loss in the hippocampus. The Enzyme-linked immunosorbent assay (ELISA) suggested that NITyr ameliorated the inflammation and oxidative stress. Consistently, NITyr could up-regulate the expressions of p-phosphadylinositol 3-kinase (PI3K) and p-Akt but not PI3K and Akt in the hippocampus. In addition to oxidative stress, CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251 could reverse the above phenomena. However, CB1 receptor antagonist AM251 could reverse oxidative stress. Accordingly, NITyr could up-regulate the expressions of CB2 but not CB1. NITyr could improve the motor coordination, learning and memory impairments, neural loss in the hippocampus and the inflammation of the mice via CB2 receptor involvement of PI3K/Akt signaling pathway.


Assuntos
Ataque Isquêmico Transitório/tratamento farmacológico , Ácidos Linoleicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Tirosina/análogos & derivados , Animais , Ansiedade/tratamento farmacológico , Gerbillinae , Hipocampo/patologia , Ácidos Linoleicos/química , Masculino , Aprendizagem em Labirinto , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Teste de Desempenho do Rota-Rod , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Tirosina/química , Tirosina/farmacologia
14.
Biol Pharm Bull ; 42(9): 1538-1544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474713

RESUMO

The analgesic effect of Ephedra Herb (EH) is believed to be derived from the anti-inflammatory action of pseudoephedrine (Pse). We recently reported that ephedrine alkaloids-free EH extract (EFE) attenuates formalin-induced pain to the same level as that achieved by EH extract (EHE), which suggests that the analgesic effect of EH may not be due to ephedrine alkaloids (EAs). To examine the contribution of EAs to the analgesic effect of EH, mice were injected with formalin to induce a biphasic pain reaction (first phase, 0-5 min; second phase, 10-45 min) at various time points after oral administration of the following test drugs: ephedrine (Eph), Pse, "authentic" EHE from Tsumura & Co. (EHE-Ts), EFE, and EHE that was used as the source of EFE (EHE-To). Biphasic pain was suppressed at 30 min after administration of Eph, EHE-Ts, and EHE-To. At 6 h after administration of EFE, EHE-To, and Pse-and at 4 to 6 h after administration of EHE-Ts-only second-phase pain was suppressed; however, the effect of Pse at 6 h was not significant. These results suggested that EHE has a biphasic analgesic effect against biphasic formalin-induced pain: in the first phase of analgesia (30 min after administration), biphasic pain is suppressed by Eph; in the second phase of analgesia (4-6 h after administration), second-phase pain is alleviated by constituents other than EAs, although Pse may partially contribute to the relief of second-phase pain.


Assuntos
Analgésicos/uso terapêutico , Ephedra/química , Efedrina/uso terapêutico , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pseudoefedrina/uso terapêutico , Administração Oral , Analgésicos/isolamento & purificação , Animais , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos , Medição da Dor , Extratos Vegetais/isolamento & purificação , Teste de Desempenho do Rota-Rod , Fatores de Tempo
15.
Arch Pharm (Weinheim) ; 352(10): e1900106, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364202

RESUMO

A series of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5-(4-Chlorophenyl)-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6c) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED50 ) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine-binding site on gamma-aminobutyric acid A (GABAA ) receptors. The results of in vivo GABA estimation and bicuculline-induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.


Assuntos
Anticonvulsivantes/síntese química , Piridinas/síntese química , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrochoque , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos Wistar , Teste de Desempenho do Rota-Rod , Convulsões/metabolismo , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/metabolismo
16.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370244

RESUMO

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Meios de Cultivo Condicionados/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Transtornos Psicomotores/tratamento farmacológico , Hemorragia Subaracnóidea/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Meios de Cultivo Condicionados/química , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Injeções Espinhais , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/fisiopatologia , Fármacos Neuroprotetores/química , Consumo de Oxigênio/efeitos dos fármacos , Transtornos Psicomotores/genética , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/fisiopatologia , Ratos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Células-Tronco/química , Células-Tronco/citologia , Células-Tronco/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/fisiopatologia , Trombose/genética , Trombose/metabolismo , Trombose/fisiopatologia , Vasoconstrição/efeitos dos fármacos
17.
BMC Neurosci ; 20(1): 40, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387538

RESUMO

BACKGROUND: Transcranial direct current stimulation (tDCS) is a noninvasive neural control technology that has become a research hotspot. To facilitate further research of tDCS, the biosafety of 500 µA cathodal tDCS, a controversial parameter in rats was evaluated. RESULTS: 24 animals were randomly divided into two groups: a cathodal tDCS group (tDCS, n = 12) and control group (control, n = 12). Animals in the tDCS group received 5 consecutive days of cathodal tDCS (500 µA, 15 min, once per day) followed by a tDCS-free interval of 2 days and 5 additional days of stimulation, totally two treatments of tDCS for a total of 10 days. Computational 3D rat model was adopted to calculate the current density distributions in brain during tDCS treatment. Essential brain functions including motor function and learning and memory ability were evaluated. Additionally, to estimate the neurotoxicity of tDCS, the brain morphology, neurotransmitter levels and cerebral temperature were investigated. Our results showed that the current density inside the brain was less than 20 A/m2 during tDCS treatment in computational model. tDCS did not affect motor functions and learning and memory ability after tDCS treatment. In addition, no significant differences were found for the tDCS group in hematology, serum biochemical markers or the morphology of major organs. Moreover, tDCS treatment had no effect on the brain morphology, neural structures, neurotransmitter levels or cerebral temperature. CONCLUSION: 500 µA cathodal tDCS as performed in the present study was safe for rodents.


Assuntos
Biomarcadores/sangue , Aprendizagem/fisiologia , Memória/fisiologia , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Segurança , Estimulação Transcraniana por Corrente Contínua/efeitos adversos , Animais , Simulação por Computador , Hipocampo/metabolismo , Testes de Função Renal , Testes de Função Hepática , Masculino , Córtex Motor/metabolismo , Córtex Motor/patologia , Neurotransmissores/metabolismo , Ratos , Teste de Desempenho do Rota-Rod , Temperatura
18.
Int Rev Neurobiol ; 146: 45-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349932

RESUMO

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50mg/kg, i.p.), equithesin (3mL/kg, i.p.) and urethane (1g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.


Assuntos
Anestésicos/efeitos adversos , Barreira Hematoencefálica/metabolismo , Edema Encefálico/fisiopatologia , Encéfalo/metabolismo , Encéfalo/patologia , Traumatismos Craniocerebrais/fisiopatologia , Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Traumatismos Craniocerebrais/metabolismo , Azul Evans/metabolismo , Radioisótopos do Iodo/metabolismo , Masculino , Destreza Motora/efeitos dos fármacos , Ratos , Teste de Desempenho do Rota-Rod , Serotonina/sangue
19.
Neurochem Int ; 129: 104502, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299418

RESUMO

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.


Assuntos
Transtornos Cognitivos/genética , Modelos Animais de Doenças , Glucosilceramidase/genética , Hipocampo/enzimologia , Doença por Corpos de Lewy/enzimologia , Animais , Córtex Cerebral/enzimologia , Comportamento Exploratório , Gliose/genética , Gliose/patologia , Glucosilceramidase/deficiência , Glucosilceramidas/metabolismo , Glicoesfingolipídeos/metabolismo , Heterozigoto , Hipocampo/patologia , Lisossomos/enzimologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Teste de Desempenho do Rota-Rod , Proteínas Vesiculares de Transporte de Acetilcolina/análise , beta-Glucosidase/deficiência
20.
Neurotox Res ; 36(3): 563-582, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286433

RESUMO

Animal models have been used to study cellular processes related to human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). The HIV-1 transgenic (Tg) rat expresses HIV viral genes except the gag-pol replication genes and exhibits neuropathological features similar to HIV patients receiving combined antiretroviral therapy (cART). Using this rat, alterations in dopaminergic function have been demonstrated; however, the data for neuroinflammation and glial reactivity is conflicting. Differences in behavior, tyrosine hydroxylase (TH) immunoreactivity, neuroinflammation, and glia reactivity were assessed in HIV-1 Tg male rats. At 6 and 12 weeks of age, rotarod performance was diminished, motor activity was not altered, and active avoidance latency performance and memory were diminished in HIV-1 Tg rats. TH+ immunoreactivity in the substantia nigra (SN) was decreased at 8 months but not at 2-5 months. At 5 months, astrocyte and microglia morphology was not altered in the cortex, hippocampus, or SN. In the striatum, astrocytes were unaltered, microglia displayed slightly thickened proximal processes, mRNA levels for Iba1 and Cd11b were elevated, and interleukin (Il)1α,Cxcr3, and cell adhesion molecule, Icam, decreased. In the hippocampus, mRNA levels for Tnfa and Cd11b were slightly elevated. No changes were observed in the cortex or SN. The data support an age-related effect of HIV proteins upon the nigrostriatal dopaminergic system and suggest an early response of microglia in the terminal synaptic region with little evidence of an associated neuroinflammatory response across brain regions.


Assuntos
Complexo AIDS Demência/patologia , Microglia/patologia , Substância Negra/enzimologia , Tirosina 3-Mono-Oxigenase/metabolismo , Complexo AIDS Demência/enzimologia , Complexo AIDS Demência/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Aprendizagem da Esquiva , Modelos Animais de Doenças , HIV-1 , Masculino , Atividade Motora , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Teste de Desempenho do Rota-Rod
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