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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(8): 814-820, 2021 Aug 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34511171

RESUMO

OBJECTIVES: To study the survival rate and the incidence of complications of very preterm infants and the factors influencing the survival rate and the incidence of complications. METHODS: The medical data of the very preterm infants with a gestational age of <32 weeks and who were admitted to the Department of Neonatology in 11 hospitals of Jiangsu Province in China from January 2018 to December 2019 were retrospectively reviewed. Their survival rate and the incidence of serious complications were analyzed. A multivariate logistic regression analysis was used to evaluate the risk factors for death and serious complications in very preterm infants. RESULTS: A total of 2 339 very preterm infants were enrolled, among whom 2 010 (85.93%) survived and 1 507 (64.43%) survived without serious complications. The groups with a gestational age of 22-25+6 weeks, 26-26+6 weeks, 27-27+6 weeks, 28-28+6 weeks, 29-29+6 weeks, 30-30+6 weeks, and 31-31+6 weeks had a survival rate of 32.5%, 60.6%, 68.0%, 82.9%, 90.1%, 92.3%, and 94.8% respectively. The survival rate tended to increase with the gestational age (P<0.05) and the survival rate without serious complications in each gestational age group was 7.5%, 18.1%, 34.5%, 52.2%, 66.7%, 75.7%, and 81.8% respectively, suggesting that the survival rate without serious complications increased with the gestational age (P<0.05). The multivariate logistic regression analysis showed that high gestational age, high birth weight, and prenatal use of glucocorticoids were protective factors against death in very preterm infants (P<0.05), and 1-minute Apgar score ≤3 was a risk factor for death in very preterm infants (P<0.05); high gestational age and high birth weight were protective factors against serious complications in very preterm infants who survived (P<0.05), while 5-minute Apgar score ≤3 and maternal chorioamnionitis were risk factors for serious complications in very preterm infants who survived (P<0.05). CONCLUSIONS: The survival rate is closely associated with gestational age in very preterm infants. A low 1-minute Apgar score (≤3) may increase the risk of death in very preterm infants, while high gestational age, high birth weight, and prenatal use of glucocorticoids are associated with the reduced risk of death. A low 5-minute Apgar score (≤3) and maternal chorioamnionitis may increase the risk of serious complications in these infants, while high gestational age and high birth weight may reduce the risk of serious complications.


Assuntos
Doenças do Prematuro , Recém-Nascido Prematuro , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Gravidez , Estudos Retrospectivos , Taxa de Sobrevida
2.
Pain ; 159(2): 273-283, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29112008

RESUMO

Pain sensitization after partial infraorbital nerve transection (p-IONX) in mice not only presents in orofacial region, but also spreads to distant body parts. The roles of toll-like receptor 4 (TLR4) in orofacial pain and the spreading process are still unclear. Here, we found that mice with deficient TLR4 because of Tr4 gene point mutation (C3H/HeJ) or spontaneous deletion (C57BL/10ScNJ) developed tactile allodynia and thermal hyperalgesia in the vibrissal pad in a parallel way to their respective wild types (C3HeB/FeJ or C57BL/6J) after p-IONX. However, allodynia in the hind paw was absent in mice with TLR4 deficiency. Pharmacological antagonism of TLR4 with LPS-RS, administered either intracisternally or intrathecally, abrogated allodynia in the hind paw without affecting the hypersensitivity in the vibrissal pad and hyperalgesia in the hind paw. Although TNF-α expression was upregulated in both the medulla and lumbar cord, the expression of TLR4 downstream molecule MyD88 increased only in the lumbar cord after p-IONX in wild types. By contrast, hind paw hypersensitivity after partial sciatic nerve ligation was significantly attenuated by TLR4 deletion. The hypersensitivity, which did not spread to the vibrissal pad, was accompanied with upregulation of MyD88 in the lumbar cord rather than in the medulla. These results suggest that TLR4 participates in the spread of allodynia component of orofacial pain to distant body sites, but not trigeminal neuropathic pain or the spread of its hyperalgesia component. This study suggests that TLR4 may serve as a potential target for the management of widespread allodynia associated with orofacial pain.


Assuntos
Hiperalgesia/etiologia , Limiar da Dor/fisiologia , Receptor 4 Toll-Like/deficiência , Neuralgia do Trigêmeo/complicações , Análise de Variância , Animais , Feminino , Hiperalgesia/tratamento farmacológico , Ligadura/efeitos adversos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/metabolismo , Medição da Dor , Mutação Puntual/genética , Nervo Isquiático/lesões , Neuropatia Ciática/fisiopatologia , Fatores de Tempo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Neuralgia do Trigêmeo/etiologia
3.
Neurochem Res ; 41(10): 2719-2727, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27350579

RESUMO

Long-term metformin treatment reduces the risk of stroke. However, the effective administration pattern and indications of metformin on acute cerebral ischemia are unclear. To investigate the neuroprotective treatment duration and dosage of metformin on focal ischemia mice and the association of neuroprotection with 5'-adenosine monophosphate-activated protein kinase (AMPK) regulations, male C57BL/6 mice were subjected to permanent or transient middle cerebral artery occlusion (MCAO) and metformin of 3, 10 and 30 mg/kg was intraperitoneally injected 1, 3 or 7 days prior to MCAO, or at the onset, or 1, 3 or 6 h after reperfusion, respectively. Infarct volumes, neurological deficit score, cell apoptosis, both total and phosphorylated AMPK expressions were assessed. Results showed that prolonged pretreatment to 7 days of metformin (10 mg/kg) significantly ameliorated brain infarct, neurological scores and cell apoptosis in permanent MCAO mice. Shorter (3 days or 1 day) or without pretreatment of metformin was not effective, suggesting a pretreatment time window. In transient MCAO mice, metformin showed no neuroprotection even with pretreatment. The expressions of total and phosphorylated AMPK were sharply decreased with effective metformin pretreatments in ischemic brains. Our data provided the first evidence that in acute ischemic injury, a 7-days pretreatment duration of 10 mg/kg metformin is necessary for its neuroprotection, and metformin may not be beneficial in the cases of blood reperfusion.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos
4.
J Neuroinflammation ; 13(1): 163, 2016 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-27342775

RESUMO

BACKGROUND: It is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain. METHODS: Neuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC(-/-) (histidine decarboxylase gene knockout) and IL-1R(-/-) (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1ß production, respectively. RESULTS: Histidine (100 mg/kg, i.p.) administered throughout days 0-3, 0-7, or 0-14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2-3, 4-7, and 8-14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1ß upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC(-/-) mice and IL-1R(-/-) mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia. CONCLUSIONS: These results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1ß production in the spinal cord following nerve injury.


Assuntos
Analgésicos/uso terapêutico , Sistema Nervoso Central/metabolismo , Histidina/uso terapêutico , Neuropatia Ciática , Analgésicos/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Cimetidina/farmacologia , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histidina/farmacologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Pirilamina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/genética , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia
5.
Pharmacology ; 97(5-6): 251-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26901681

RESUMO

BACKGROUND AND METHODS: Pregabalin alleviates stimulus-evoked neuropathic pain (NeuP) in some pain patients and rodents in models of painful neuropathies. But it is not known if pregabalin can also alleviate spontaneous NeuP. Sciatic and saphenous neurectomy in rats elicits spontaneous self-mutilation of the denervated hindpaw, a behavior that models spontaneous NeuP. We tested if pregabalin (20 or 30 mg/kg/day; twice daily, per os) for 7 days before denervation, or 42 days thereafter, can suppress this behavior. RESULTS: Compared with the vehicle, pregabalin administered in both treatment regimens markedly and significantly delayed autotomy onset and suppressed its levels for weeks after treatment cessation. CONCLUSIONS: At doses known to effectively suppress stimulus-evoked pain in rats, pregabalin can prevent development of spontaneous NeuP and suppress it postoperatively.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/prevenção & controle , Pregabalina/administração & dosagem , Pregabalina/uso terapêutico , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Nervo Isquiático/lesões
6.
Pain ; 157(3): 740-749, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26588696

RESUMO

Clinical studies show that chronic pain can spread to adjacent or even distant body regions in some patients. However, little is known about how this happens. In this study, we found that partial infraorbital nerve transection (p-IONX) in MRL/MPJ mice induced not only marked and long-lasting orofacial thermal hyperalgesia but also thermal hyperalgesia from day 3 postoperatively (PO) and tactile allodynia from day 7 PO in bilateral hind paws. Pain sensitization in the hind paw was negatively correlated with facial thermal hyperalgesia at early but not late stage after p-IONX. After a rapid activation of c-Fos, excitability and excitatory synaptic neurotransmission in lumbar dorsal horn neurons were elevated from day 3 and day 7 PO, respectively. In addition, microglial activation after p-IONX transmitted caudally from the Vc in the medulla to lumber dorsal horn in a time-dependent manner. Inhibition of microglial activation by minocycline at early but not late stage after p-IONX postponed and attenuated pain sensitization in the hind paw. These results indicate that neuropathic pain after p-IONX in MRL/MPJ mice spreads from the orofacial region to distant somatic regions and that a rostral-caudal transmission of central sensitization in the spinal cord is involved in the spreading process of pain hypersensitivity.


Assuntos
Hiperalgesia/patologia , Nervo Maxilar/lesões , Neuralgia/patologia , Medição da Dor , Animais , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Neuralgia/etiologia , Neuralgia/metabolismo , Técnicas de Cultura de Órgãos , Medição da Dor/métodos , Limiar da Dor/fisiologia
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 44(3): 315-22, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26350013

RESUMO

OBJECTIVE: To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS). METHODS: The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively. RESULTS: Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01). CONCLUSION: The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.


Assuntos
Anticonvulsivantes , Estimulação Elétrica , Hipocampo/fisiopatologia , Excitação Neurológica , Convulsões/fisiopatologia , Animais , Epilepsia , Camundongos
8.
Sci Rep ; 5: 12079, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26174710

RESUMO

Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.


Assuntos
Transtornos Cognitivos/prevenção & controle , Minociclina/farmacologia , Fármacos Neuroprotetores/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Lesões das Artérias Carótidas/complicações , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Transtornos Cognitivos/etiologia , Demência Vascular/metabolismo , Demência Vascular/patologia , Modelos Animais de Doenças , Fase G2 , Oxirredutases Intramoleculares/farmacologia , Lipopolissacarídeos/farmacologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microscopia Eletrônica , Oligodendroglia/citologia , Ratos , Ratos Sprague-Dawley , Fase S , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Substância Branca/fisiologia
9.
Neurosci Lett ; 588: 95-100, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25562630

RESUMO

Febrile seizures (FSs) are the most common type of convulsions in childhood and complex FSs represent an increased risk for development of temporal lobe epilepsy. The aim of this study was to analyze the anticonvulsant effects of carnosine, an endogenous dipeptide composed of alanine and histidine, on hyperthermia induced seizure in immature mice. Injection of carnosine significantly increased the latency and decreased the duration of FSs in a dose-dependent manner. In addition, histidine had similar effects on FSs as carnosine. The protective effect of carnosine or histidine was completely abolished by α-fluoromethylhistidine (α-FMH), a selective and irreversible histidine decarboxylase inhibitor, or in histidine decarboxylase deficient (HDC-KO) mice. Peripheral carnosine administration increased the level of carnosine, histidine and histamine in the cortex and hippocampus of mice pups, but decreased glutamate contents in the cortex and hippocampus. These results indicate that carnosine can protect against FSs in mice pups through its conversion to histamine, suggesting that it may serve as an efficient anti-FSs drug in the future.


Assuntos
Anticonvulsivantes/uso terapêutico , Carnosina/uso terapêutico , Convulsões Febris/prevenção & controle , Animais , Anticonvulsivantes/metabolismo , Carnosina/metabolismo , Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Histamina/metabolismo , Histidina/metabolismo , Histidina/uso terapêutico , Histidina Descarboxilase/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Convulsões Febris/metabolismo , Ácido gama-Aminobutírico/metabolismo
10.
Autophagy ; 10(10): 1801-13, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25126734

RESUMO

Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Estresse do Retículo Endoplasmático , Mitofagia , Fármacos Neuroprotetores/uso terapêutico , Tapsigargina/uso terapêutico , Tunicamicina/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glucose/deficiência , Camundongos , Mitofagia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tapsigargina/farmacologia , Tunicamicina/farmacologia
11.
CNS Neurosci Ther ; 20(10): 883-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24990156

RESUMO

INTRODUCTION: The upregulation of Nav1.8 in primary afferents plays a critical role in the development and persistence of neuropathic pain. The mechanisms underlying the upregulation are not fully understood. AIMS: The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain. RESULTS: Histamine at 10(-8) M increased the expression of Nav1.8 in cultured DRG neurons. This effect could be blocked by H2 receptor antagonist cimetidine or famotidine, but not by H1 receptor antagonist pyrilamine or dual H3 /H4 antagonist thioperamide. Peri-sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4/L5 DRG neurons in a dose-dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40 mg/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve. CONCLUSIONS: Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H2 receptor-mediated pathway and thereby contributes to neuropathic pain. H2 receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Receptores Histamínicos H2/metabolismo , Ciática/patologia , Células Receptoras Sensoriais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Famotidina/farmacologia , Gânglios Espinais/citologia , Histamina/uso terapêutico , Agonistas dos Receptores Histamínicos/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
J Cereb Blood Flow Metab ; 34(2): 275-83, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24192637

RESUMO

Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO2 for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO2 for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO3 significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen-glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis.


Assuntos
Acidose , Dióxido de Carbono/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão , Bicarbonato de Sódio/sangue , Acidente Vascular Cerebral , Acidose/sangue , Acidose/induzido quimicamente , Acidose/tratamento farmacológico , Animais , Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/fisiopatologia , Masculino , Camundongos , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
13.
Zhonghua Yi Xue Za Zhi ; 93(22): 1691-5, 2013 Jun 11.
Artigo em Chinês | MEDLINE | ID: mdl-24124673

RESUMO

OBJECTIVE: To explore the protective effects of beraprost plus simvastatin on monocrotaline-induced pulmonary arterial hypertension in rats. METHODS: Forty male Sprague-Dawley rats were allocated to control (C), untreated pulmonary arterial hypertension (P), beraprost (B), simvastatin (S) and combination groups (Com) (n = 8 each). Normal saline was injected subcutaneously into group C and then there was no other intervention for 21 days. Group P, B, S and Com rats received subcutaneous injections of monocrotaline (MCT, 60 mg/kg) and then isovolumetric normal saline, beraprost (100 µg·kg(-1)·d(-1)), simvastatin (2 mg·kg(-1)·d(-1)) and beraprost (100 µg·kg(-1)·d(-1)) plus simvastatin (2 mg·kg(-1)·d(-1)) by daily gastric lavage for 21 days. At Day 22, heart rate (HR), mean arterial pressure (MAP) and mean pulmonary pressure (mPAP) were detected and right heart ventricular hypertrophy index (RVHI) was calculated. The histopathology changes and tunica media thickness percentage of pulmonary arteries (WT%) were evaluated by pulmonary tissue staining. The results were analyzed statistically. RESULTS: The differences of HR and MAP were not significant among 5 groups (all P > 0.05). The levels of mPAP, RVHI and WT% in group B ((27.4 ± 3.7) mm Hg, 0.35 ± 0.03, 26.7% ± 2.4%), group S ((29.9 ± 4.4) mm Hg, 0.36 ± 0.03, 28.2% ± 1.9%) and group Com ((23.1 ± 3.9) mm Hg, 0.32 ± 0.03, 17.4% ± 3.3%) were lower than those in group P ((35.4 ± 5.7) mm Hg, 0.41 ± 0.05, 42.8% ± 5.9%) (all P < 0.05). CONCLUSIONS: The combined use of beraprost and simvastatin may delay the increase of mPAP and remodeling of pulmonary vessels and inhibit right ventricular hypertrophy in pulmonary arterial hypertension rats. Its efficacy is superior to that of monotherapy.


Assuntos
Epoprostenol/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Sinvastatina/uso terapêutico , Animais , Quimioterapia Combinada , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/induzido quimicamente , Masculino , Monocrotalina/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
14.
CNS Neurosci Ther ; 19(9): 649-58, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23773488

RESUMO

AIMS: To explore the role of histamine in acute pain perception and its possible mechanisms. METHODS: Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav 1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC(-/-) ) mice and their wild-types. RESULTS: HDC(-/-) mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with α-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav 1.8 expression in primary afferent neurons was increased both in HDC(-/-) and in α-FMH-treated wild-type mice. A higher Nav 1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC(-/-) mice. Nav 1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. CONCLUSION: Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav 1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.


Assuntos
Histamina/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.8/fisiologia , Neurônios Aferentes/fisiologia , Nociceptividade/fisiologia , Potenciais de Ação , Doença Aguda , Animais , Gânglios Espinais/fisiologia , Histidina Descarboxilase/fisiologia , Metilistidinas/farmacologia , Camundongos , Tetrodotoxina/farmacologia
15.
Neurosci Lett ; 549: 69-73, 2013 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-23791924

RESUMO

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.


Assuntos
Astrócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutamato-Amônia Ligase/metabolismo , Histamina/farmacologia , Animais , Astrócitos/citologia , Astrócitos/enzimologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/enzimologia , Relação Dose-Resposta a Droga , Glucose/metabolismo , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley
16.
Neurosci Bull ; 29(3): 261-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23494529

RESUMO

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 µg/5 µL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.


Assuntos
Analgésicos/farmacologia , Histamina/farmacologia , Neuralgia/tratamento farmacológico , Animais , Axotomia , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Neuroma/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
CNS Neurosci Ther ; 18(9): 745-53, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22943141

RESUMO

AIMS: Recently, we found carnosine protects against N-Methyl-D-Aspartate (NMDA) induced excitotoxicity through a histaminergic pathway. The aim of this study was to determine whether the carnosine-histidine-histamine pathway also played a protective role in subcortical ischemic vascular dementia (SIVD). METHODS: Adult male mice (C57BL/6 strain) were subjected to right unilateral common carotid arteries occlusion (rUCCAO) and treated with carnosine or histidine. Object recognition test, passive avoidance task, Morris water maze, and immunohistochemical analyses were performed after rUCCAO. RESULTS: We found that carnosine (200, 500 mg/kg) ameliorated white matter lesion and cognitive impairment evaluated by object recognition test, passive avoidance task, and Morris water maze test after rUCCAO in both wide-type mice and histidine decarboxylase knockout mice, which are lack of endogenous histamine. However, administration of histidine did not show the same effect. The myelin basic protein in the corpus callosum decreased obviously at day 37 after rUCCAO, which was largely reversed by carnosine (200, 500 mg/kg). Carnosine (200, 500 mg/kg) suppressed the activation of microglia and astrocyte as attenuating the elevation of glial fibrillary acidic protein (GFAP) and Iba-1 fluorescent intensity. Moreover, carnosine (200, 500 mg/kg) significantly attenuated the increase in reactive oxygen species generation after rUCCAO. CONCLUSION: These data suggest that the neuroprotective effect of carnosine on rUCCAO in mice is not dependent on the histaminergic pathway, but may be due to a suppression of reactive oxygen species generation, glia activation, and myelin degeneration.


Assuntos
Carnosina/farmacologia , Demência Vascular/tratamento farmacológico , Histamina/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/metabolismo , Demência Vascular/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Histidina/farmacologia , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos
18.
Neurobiol Dis ; 48(1): 20-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22659307

RESUMO

Low-frequency stimulation (LFS) has been considered as an option for the treatment of intractable epilepsy. However, previous data showed that LFS of certain brain regions only exerts its effect within a very narrow therapeutic time window, which lasts from seconds to tens of seconds, thus restricting its clinical application. The present study was designed to determine whether there exists a target with a wider therapeutic window for LFS treatment. Therefore, evoked seizures in the rat were induced by amygdala kindling and spontaneous seizures were induced by pilocarpine. The effects of different modes of LFS at the subiculum on the progression and severity of evoked seizures and the frequency of spontaneous seizure were evaluated. We found that (i) LFS at 1Hz delivered to the subiculum before and immediately after the kindling stimulations, or after the cessation of afterdischarge (afterdischarge duration, ADD) decreased the seizure stages and shortened the ADD both in seizure acquisition and expression in amygdaloid-kindled seizures. In addition, even LFS delivered after duration of double the ADD prolonged the kindling progression. (ii) LFS delivered at 1Hz, but not 0.5, 3 or 130Hz, immediately after the cessation of kindling stimulations retarded the progression of kindling seizures. (iii) Pilocarpine-induced spontaneous seizures were completely inhibited by 1Hz LFS. Thus, these results demonstrated that LFS of the subiculum has a wide therapeutic time-window for temporal lobe epilepsy treatment in rats, suggesting that the subiculum may be a promising and suitable target for clinical application.


Assuntos
Estimulação Encefálica Profunda/métodos , Epilepsia do Lobo Temporal/terapia , Hipocampo/fisiopatologia , Excitação Neurológica/fisiologia , Tonsila do Cerebelo/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Eletrodos Implantados , Epilepsia do Lobo Temporal/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
19.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 41(1): 47-53, 2012 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-22419463

RESUMO

OBJECTIVE: To investigate the effects of epileptogenesis and low frequency stimulation at epileptic focus on spontaneous neuropathic pain in rats. METHODS: Bipolar stimulating electrodes were implanted in the amygdala and current with constant intensity was applied to evoke kindling-induced seizures. In partial and generalized stages of seizure acquisition, neuroma model of spontaneous neuropathic pain was prepared by completely transection of the left sciatic and saphenous nerves of rats. Autotomy behavior was scored daily until d 63 postoperatively. Rats were divided into 5 groups: Control (n=7), rats with partial seizures (1-3 stages, n=5), rats with generalized seizures (4-5 stages, n=7), rats with partial seizures and low frequency stimulation(n=4), rats with generalized seizures and low frequency stimulation(n=4). Low frequency stimulation was applied to the amygdala, the epileptic focus for 21 d from the d 2 after nerve transection. RESULTS: Autotomy level in rats with partial seizures was significantly lower than that in controls. The autotomy scores during postoperative d 40 ≊63 were significantly lower than those of controls, the area under the progression curve of autotomy behavior was decreased from 308.2 ±51.57 to 45.80 ±24.64, the onset day of autotomy was postponed by 32 d and none of the animals with partial seizures showed high autotomy, while 71.4 % of controls showed that on d 63 postoperatively. Rats with generalized seizures showed autotomy similar to controls, except that the onset day was postponed by 16 d. Autotomy behavior in rats receiving low frequency stimulation of the amygdala was not different from that in controls. CONCLUSION: Focal seizures can lower sensitivity to spontaneous neuropathic pain in rats, while low frequency stimulation applied to the focus can abolish such effect.


Assuntos
Epilepsia/complicações , Excitação Neurológica , Neuralgia/etiologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica/efeitos adversos , Epilepsia/etiologia , Masculino , Ratos , Ratos Sprague-Dawley
20.
J Orthop Sci ; 16(5): 598-605, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21833614

RESUMO

BACKGROUND: Low-magnitude vibration has been widely used as a tool for rehabilitation, enhancing physical performance, and stimulating bone development. Although mechanical stimulation generated by vibrations is regarded as important factor in bone remodeling, the underlying cellular and molecular regulatory mechanisms of this response, which may be important in the development of new mechanobiological strategies, currently remain unclear. METHODS: In this study, to investigate the mechanobiological mechanisms of vibration-enhanced osteogenic responses in osteoblasts, MC3T3-E1 cells were subjected to vibrations of different amplitude (0.06, 0.14, 0.32, 0.49, 0.66, and 0.8 × g) at 40 Hz for 30 min/day over 3 days. The osteogenesis-related transcription factors Wnt10B, Sclerostin, OPG, and RANKL were analyzed for mRNA and protein expression. RESULTS: The results revealed that protein expression of Wnt10B and OPG was increased in a magnitude-dependent manner by mechanical vibrations at amplitudes of 0.06, 0.14, 0.32, and 0.49 × g; the maximum increases were 2.4-fold (p < 0.001) and 7.9-fold (p < 0.001), respectively, at 0.49 × g. Sclerostin and RANKL levels were reduced at all amplitudes. On the basis of mRNA levels, the reduced expression of RANKL was further downregulated (p < 0.05) whereas OPG expression was further increased (p < 0.01) when the MC3T3-E1 cells were treated with LiCl compared with the effects of vibration alone. CONCLUSIONS: The findings may indicate that Wnt signaling is involved in mechanotransduction at low-magnitude vibration; this may provide a cellular basis, and impetus for further development of, biomechanically based intervention for enhancing bone strength and accelerating implant osseointegration.


Assuntos
Mecanotransdução Celular/fisiologia , Osteoblastos/fisiologia , Proteínas Wnt/fisiologia , Via de Sinalização Wnt/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Western Blotting , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Marcadores Genéticos , Humanos , Osteoprotegerina/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ligante RANK/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Vibração , Proteínas Wnt/metabolismo
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