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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Biology (Basel) ; 10(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439951

RESUMO

Inadequate activation of cell cycle proteins including cyclin D1 and cdk4 is involved in neuronal cell death induced by diverse pathological stresses, including transient global brain ischemia. The neuroprotective effect of ischemic preconditioning is well-established, but the underlying mechanism is still unknown. In this study, we examined changes in cyclin D1, cdk4, and related molecules in cells or neurons located in Cornu Ammonis 1 (CA1) of gerbil hippocampus after transient ischemia for 5 min (ischemia and reperfusion) and investigated the effects of IPC on these molecules after ischemia. Four groups were used in this study as follows: sham group, ischemia group, IPC plus (+) sham group, and IPC+ischemia group. IPC was developed by inducing 2-min ischemia at 24 h before 5-min ischemia (real ischemia). Most pyramidal cells located in CA1 of the ischemia group died five days after ischemia. CA1 pyramidal cells in the IPC+ischemia group were protected. In the ischemia group, the expressions of cyclin D1, cdk4, phosphorylated retinoblastoma (p-Rb), and E2F1 (a transcription factor regulated by p-Rb) were significantly altered in the pyramidal cells with time after ischemia; in the IPC+ischemia group, they were controlled at the level shown in the sham group. In particular, the expression of p16INK4a (an endogenous cdk inhibitor) in the ischemia group was reversely altered in the pyramidal cells; in the IPC+TI group, the expression of p16INK4a was not different from that shown in the sham group. Our current results indicate that cyclin D1/cdk4-related signals may have important roles in events in neurons related to damage/death following ischemia and reperfusion. In particular, the preservation of p16INK4a by IPC may be crucial in attenuating neuronal death/damage or protecting neurons after brain ischemic insults.

3.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34212986

RESUMO

Tumor necrosis factor (TNF)­α and TNF receptor 1 (TNF­R1) play diverse roles in modulating the neuronal damage induced by cerebral ischemia. The present study compared the time­dependent changes of TNF­α and TNF­R1 protein expression levels in the hippocampal subfield cornu ammonis 1 (CA1) between adult and young gerbils following transient forebrain ischemia (tFI), via western blot and immunohistochemistry analyses. In adult gerbils, delayed neuronal death of pyramidal neurons, the principal neurons in CA1, was recorded 4 days after tFI; however, in young gerbils, delayed neuronal death was recorded 7 days after tFI. TNF­α protein expression levels gradually increased in both groups following tFI; however, TNF­α expression was higher in young gerbils compared with adult gerbils. TNF­R1 protein expression levels markedly increased in both groups 1 day after tFI. Subsequently, TNF­R1 expression gradually decreased in young gerbils, whereas TNF­R1 expression levels were irregularly altered in adult gerbils following tFI. Notably, TNF­α immunoreactivity significantly increased in pyramidal neurons in both groups 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF­α immunoreactivity was rarely exhibited in pyramidal neurons 4 days after tFI due to neuronal death, suggesting that TNF­α immunoreactivity was newly expressed in astrocytes. In young gerbils, TNF­α immunoreactivity increased in pyramidal neurons 4 days after tFI, and TNF­α immunoreactivity was newly expressed in astrocytes. In addition, TNF­R1 immunoreactivity was exhibited in pyramidal cells of both sham groups, and significantly increased 1 day after tFI; however, the patterns altered between both groups. In adult gerbils, TNF­R1 immunoreactivity was rarely exhibited 4 days after tFI, and astrocytes newly expressed TNF­R1 immunoreactivity. In young gerbils, TNF­R1 immunoreactivity increased in pyramidal neurons 4 days after tFI; however, TNF­R1 immunoreactivity was not reported in pyramidal neurons and astrocytes thereafter. Taken together, the results of the present study suggest that different expression levels of TNF­α and TNF­R1 in ischemic CA1 between adult and young gerbils may be due to age­dependent differences of tFI­induced neuronal death.

4.
Neurochem Res ; 46(11): 2852-2866, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34050880

RESUMO

Transient ischemia in the brain causes blood-brain barrier (BBB) breakdown and dysfunction, which is related to ischemia-induced neuronal damage. Leakage of plasma proteins following transient ischemia is one of the indicators that is used to determine the extent of BBB dysfunction. In this study, neuronal damage/death, leakage of albumin and IgG, microgliosis, and inflammatory cytokine expression were examined in the hippocampal CA1 region, which is vulnerable to transient ischemia, following 5-min (mild) and 15-min (severe) ischemia in gerbils induced by transient common carotid arteries occlusion (tCCAo). tCCAo-induced neuronal damage/death occurred earlier and was more severe after 15-min tCCAo vs. after 5-min tCCAo. Significant albumin and IgG leakage (albumin and IgG immunoreactivity) took 1 or 2 days to begin, and immunoreactivity was markedly increased 5 days after 5-min tCCAo. While, albumin and IgG leakage began to increase 6 h after 15-min tCCAo and remained significantly higher over time than that seen in 5-min tCCAo. IgG immunoreactivity was observed in degenerating neurons and activated microglia after tCCAo, and microglia were activated to a greater extent after 15-min tCCAo than 5-min tCCAo. In addition, following 15-min tCCAo, pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß)] immunoreactivity was significantly higher than that seen following 5-min tCCAo, whereas immunoreactivity of anti-inflammatory cytokines (IL-4 and IL-13) was lower in 15-min than 5-min tCCAo. These results indicate that duration of tCCAo differentially affects the timing and degree of neuronal damage or loss, albumin and IgG leakage and inflammatory cytokine expression in brain tissue. In addition, more severe BBB leakage is closely related to acceleration of neuronal damage through increased microglial activation and pro-inflammatory cytokine expression in the ischemic hippocampal CA1 region.

5.
Antioxidants (Basel) ; 10(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924188

RESUMO

Salicin is a major natural compound of willow bark and displays diverse beneficial biological properties, such as antioxidant activity. However, little information available for the neuroprotective potential of salicin against ischemic brain injury has been reported. Thus, this study was performed to investigate the neuroprotective potential of salicin against ischemia and reperfusion (IR) injury and its mechanisms in the hippocampus using a gerbil model of 5-min transient ischemia (TI) in the forebrain, in which a massive loss (death) of pyramidal neurons cells occurred in the subfield Cornu Ammonis 1 (CA1) among the hippocampal subregions (CA1-3) at 5 days after TI. To examine neuroprotection by salicin, gerbils were pretreated with salicin alone or together with LY294002, which is a phosphatidylinositol 3-kinase (PI3K) inhibitor, once daily for 3 days before TI. Treatment with 20 mg/kg of salicin significantly protected CA1 pyramidal neurons against the ischemic injury. Treatment with 20 mg/kg of salicin significantly reduced the TI-induced increase in superoxide anion generation and lipid peroxidation in the CA1 pyramidal neurons after TI. The treatment also reinstated the TI-induced decrease in superoxide dismutases (SOD1 and SOD2), catalase, and glutathione peroxidase in the CA1 pyramidal cells after TI. Moreover, salicin treatment significantly elevated the levels of phosphorylation of Akt and glycogen synthase kinase-3ß (GSK3ß), which is a major downstream target of PI3K, in the ischemic CA1. Notably, the neuroprotective effect of salicin was abolished by LY294002. Taken together, these findings clearly indicate that salicin protects against ischemic brain injury by attenuating oxidative stress and activating the PI3K/Akt/GSK3ß pathway.

6.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921375

RESUMO

It has been studied that the damage or death of neurons in the hippocampus is different according to hippocampal subregions, cornu ammonis 1-3 (CA1-3), after transient ischemia in the forebrain, showing that pyramidal neurons located in the subfield CA1 (CA1) are most vulnerable to this ischemia. Hyperthermia is a proven risk factor for brain ischemia and can develop more severe and extensive brain damage related with mortality rate. It is well known that heme oxygenase-1 (HO-1) activity and expression is increased by various stimuli in the brain, including hyperthermia. HO-1 can be either protective or deleterious in the central nervous system, and its roles depend on the expression levels of enzymes. In this study, we investigated the effects of hyperthermia during ischemia on HO-1 expression and neuronal damage/death in the hippocampus to examine the relationship between HO-1 and neuronal damage/death following 5-min transient ischemia in the forebrain using gerbils. Gerbils were assigned to four groups: (1) sham-operated gerbils with normothermia (Normo + sham group); (2) ischemia-operated gerbils with normothermia (Normo + ischemia group); (3) sham-operated gerbils with hyperthermia (39.5 ± 0.2 °C) during ischemia (Hyper + sham group); and (4) ischemia-operated gerbils with hyperthermia during ischemia (Hyper + ischemia group). HO-1 expression levels in CA1-3 of the Hyper + ischemia group were significantly higher than those in the Normo + ischemia group. HO-1 immunoreactivity in the Hyper + ischemia group was significantly increased in pyramidal neurons and astrocytes with time after ischemia, and the immunoreactivity was significantly higher than that in the Normo + ischemia group. In the Normo + Ischemia group, neuronal death was shown in pyramidal neurons located only in CA1 at 5 days after ischemia. However, in the Hyper + ischemia group, pyramidal neuronal death occurred in CA1-3 at 2 days after ischemia. Taken together, our findings showed that brain ischemic insult during hyperthermic condition brings up earlier and severer neuronal damage/death in the hippocampus, showing that HO-1 expression in neurons and astrocytes is different according to brain subregions and temperature condition. Based on these findings, we suggest that hyperthermia in patients with ischemic stroke must be taken into the consideration in the therapy.


Assuntos
Lesões Encefálicas/genética , Heme Oxigenase-1/genética , Hipocampo/metabolismo , Traumatismo por Reperfusão/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Gerbillinae/genética , Gerbillinae/metabolismo , Hipocampo/lesões , Hipocampo/fisiopatologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Traumatismo por Reperfusão/patologia
7.
Molecules ; 26(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918660

RESUMO

Angelica gigas Nakai root contains decursin which exerts beneficial properties such as anti-amnesic and anti-inflammatory activities. Until now, however, the neuroprotective effects of decursin against transient ischemic injury in the forebrain have been insufficiently investigated. Here, we revealed that post-treatment with decursin and the root extract saved pyramidal neurons in the hippocampus following transient ischemia for 5 min in gerbil forebrain. Through high-performance liquid chromatography, we defined that decursin was contained in the extract as 7.3 ± 0.2%. Based on this, we post-treated with 350 mg/kg of extract, which is the corresponding dosage of 25 mg/kg of decursin that exerted neuroprotection in gerbil hippocampus against the ischemia. In addition, behavioral tests were conducted to evaluate ischemia-induced dysfunctions via tests of spatial memory (by the 8-arm radial maze test) and learning memory (by the passive avoidance test), and post-treatment with the extract and decursin attenuated ischemia-induced memory impairments. Furthermore, we carried out histochemistry, immunohistochemistry, and double immunohistofluorescence. Pyramidal neurons located in the subfield cornu ammonis 1 (CA1) among the hippocampal subfields were dead at 5 days after the ischemia; however, treatment with the extract and decursin saved the pyramidal neurons after ischemia. Immunoglobulin G (IgG, an indicator of extravasation), which is not found in the parenchyma in normal brain tissue, was apparently shown in CA1 parenchyma from 2 days after the ischemia, but IgG leakage was dramatically attenuated in the CA1 parenchyma treated with the extract and decursin. Furthermore, astrocyte endfeet, which are a component of the blood-brain barrier (BBB), were severely damaged at 5 days after the ischemia; however, post-treatment with the extract and decursin dramatically attenuated the damage of the endfeet. In brief, therapeutic treatment of the extract of Angelica gigas Nakai root and decursin after 5 min transient forebrain ischemia protected hippocampal neurons from the ischemia, showing that ischemia-induced BBB leakage and damage of astrocyte endfeet was significantly attenuated by the extract and decursin. Based on these findings, we suggest that Angelica gigas Nakai root containing decursin can be employed as a pharmaceutical composition to develop a therapeutic strategy for brain ischemic injury.


Assuntos
Angelica/química , Astrócitos/patologia , Benzopiranos/uso terapêutico , Barreira Hematoencefálica/patologia , Butiratos/uso terapêutico , Ataque Isquêmico Transitório/patologia , Extratos Vegetais/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzopiranos/química , Benzopiranos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Butiratos/química , Butiratos/farmacologia , Gerbillinae , Proteína Glial Fibrilar Ácida/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Imunoglobulina G/metabolismo , Masculino , Neuraminidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/farmacologia , Padrões de Referência , Memória Espacial/efeitos dos fármacos
8.
Cells ; 10(1)2021 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401719

RESUMO

Autonomic dysfunction in the central nervous system (CNS) can cause death after recovery from a cardiac arrest (CA). However, few studies on histopathological changes in animal models of CA have been reported. In this study, we investigated the prevalence of neuronal death and damage in various brain regions and the spinal cord at early times after asphyxial CA and we studied the relationship between the mortality rate and neuronal damage following hypothermic treatment after CA. Rats were subjected to 7-8 min of asphyxial CA, followed by resuscitation and prompt hypothermic treatment. Eight regions related to autonomic control (the cingulate cortex, hippocampus, thalamus, hypothalamus, myelencephalon, and spinal cord) were examined using cresyl violet (a marker for Nissl substance) and Fluoro-Jade B (a marker for neuronal death). The survival rate was 44.5% 1 day post-CA, 18.2% 2 days post-CA and 0% 5 days post-CA. Neuronal death started 12 h post-CA in the gigantocellular reticular nucleus and caudoventrolateral reticular nucleus in the myelencephalon and lamina VII in the cervical, thoracic, lumbar, and sacral spinal cord, of which neurons are related to autonomic lower motor neurons. In these regions, Iba-1 immunoreactivity indicating microglial activation (microgliosis) was gradually increased with time after CA. Prompt hypothermic treatment increased the survival rate at 5 days after CA with an attenuation of neuronal damages and death in the damaged regions. However, the survival rate was 0% at 12 days after CA. Taken together, our study suggests that the early damage and death of neurons related to autonomic lower motor neurons was significantly related to the high mortality rate after CA and that prompt hypothermic therapy could increase the survival rate temporarily after CA, but could not ultimately save the animal.


Assuntos
Sistema Nervoso Autônomo/patologia , Sistema Nervoso Central/patologia , Parada Cardíaca/patologia , Hipotermia Induzida , Neurônios/patologia , Animais , Antígenos Nucleares/metabolismo , Morte Celular , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Ratos Sprague-Dawley , Análise de Sobrevida , Fatores de Tempo
9.
Int J Mol Sci ; 22(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498705

RESUMO

It has been reported that CD200 (Cluster of Differentiation 200), expressed in neurons, regulates microglial activation in the central nervous system, and a decrease in CD200 expression causes an increase in microglial activation and neuronal loss. The aim of this study was to investigate time-dependent changes in CD200 expression in the hippocampus proper (CA1, 2, and 3 fields) after transient forebrain ischemia for 5 min in gerbils. In this study, 5-min ischemia evoked neuronal death (loss) of pyramidal neurons in the CA1 field, but not in the CA2/3 fields, at 5 days postischemia. In the sham group, CD200 expression was found in pyramidal neurons of the CA1 field, and the immunoreactivity in the group with ischemia was decreased at 6 h postischemia, dramatically increased at 12 h postischemia, decreased (to level found at 6 h postischemia) at 1 and 2 days postischemia, and significantly increased again at 5 days postischemia. At 5 days postischemia, CD200 immunoreactivity was strongly expressed in microglia and GABAergic neurons. However, in the CA3 field, the change in CD200 immunoreactivity in pyramidal neurons was markedly weaker than that in the CA1 field, showing there was no expression of CD 200 in microglia and GABAergic neurons. In addition, treatment of 10 mg/kg risperidone (an atypical antipsychotic drug) after the ischemia hardly changed CD200 immunoreactivity in the CA1 field, showing that CA1 pyramidal neurons were protected from the ischemic injury. These results indicate that the transient ischemia-induced change in CD200 expression may be associated with specific and selective neuronal death in the hippocampal CA1 field following transient forebrain ischemia.


Assuntos
Antígenos CD/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Risperidona/farmacologia , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Gerbillinae , Ataque Isquêmico Transitório/patologia , Masculino , Microglia/patologia , Prosencéfalo/irrigação sanguínea , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia
10.
Mol Med Rep ; 22(2): 1317-1324, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627009

RESUMO

Neuroinflammation is a primary characteristic of the aging brain. During normal aging, macrophage inflammatory protein­3α (MIP­3α) and its receptor C­C chemokine receptor type 6 (CCR6) serve pivotal roles in the neuroinflammatory process in the brain. The aim of the present study was to investigate age­dependent alterations in the immunoreactivity of MIP­3α and CCR6 in the gerbil hippocampus at postnatal month (PM) 1, 6, 12 and 24 via immunohistochemistry. In the PM 1 group, both MIP­3α and CCR6 immunoreactivity were observed primarily in the stratum pyramidale in the hippocampus proper and in the granule cell layer in the dentate gyrus. In the PM 6 and PM 12 groups, MIP­3α in the stratum pyramidale and granule cell layer was decreased compared with the PM 1 group, and CCR6 immunoreactivity in both layers was faint. In the PM 24 group, MIP­3α expression in the stratum pyramidale and granule cell layer was higher than that in the PM 1 group, and CCR6 immunoreactivity in both layers was increased compared with the PM 12 group; however, it was decreased compared with the PM 1 group. In conclusion, MIP­3α and CCR6 immunoreactivity were altered in the hippocampus during normal aging. The results of the current study suggested that age­dependent alterations of MIP­3α and CCR6 may be associated with age­related neuroinflammation in the hippocampus.


Assuntos
Envelhecimento/metabolismo , Quimiocina CCL20/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Receptores CCR6/metabolismo , Animais , Gerbillinae , Masculino , Microglia/citologia , Microglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo
11.
Neurochem Res ; 45(10): 2352-2363, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32671629

RESUMO

It is questionable whether intermittent fasting (IF) protects against brain ischemic injury. This study examined whether IF increased anti-inflammatory cytokines and protected neurons from ischemia-reperfusion injury in the gerbil hippocampus. Gerbils were subjected to 1-day alternating fasting as IF for 1, 2, or 3 months and assigned to sham or 5 min of transient ischemia. We examined the changes in anti-inflammatory cytokines (IL-4 and IL-13), neurons and IgG by immunohistochemistry or immunofluorescence staining in the cornu ammonis 1 (CA1) region of the hippocampus before and after ischemia. IF increased IL-13 immunoreactivity in the CA1 region before ischemia, but did not affect IL-4 immunoreactivity. After ischemia, IL-13 and 4 immunoreactivities in the CA1 region were significantly lower in IF gerbils than in non-IF gerbils. In the IF gerbils, the CA1 pyramidal neurons were not protected from ischemic injury; in these gerbils, strong IgG immunoreactivity was seen in the CA1 parenchyma, indicating leakage of the BBB. In brief, IF increased IL-13 in the CA1 region, but these neurons were not protected from transient ischemic injury evidenced by IgG immunoreactivity in the CA1 parenchyma. This study indicates that IF increased some anti-inflammatory cytokines but did not afford neuroprotection against ischemic insults via BBB disruption.


Assuntos
Barreira Hematoencefálica/metabolismo , Jejum/fisiologia , Hipocampo/fisiopatologia , Interleucina-13/metabolismo , Células Piramidais/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Gerbillinae , Hipocampo/metabolismo , Masculino , Traumatismo por Reperfusão/metabolismo
12.
Iran J Basic Med Sci ; 23(2): 202-205, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32405363

RESUMO

Objectives: Nuclear receptor-related protein 1 (Nurr1), one of immediate-early genes, is a member of orphan nuclear receptor family. The aim of this study was to investigate the time-dependent change of Nurr1 protein expression in the mouse hippocampal CA3 region following kainic acid (KA)-induced excitotoxic neuronal damage. Materials and Methods: Male ICR mice were used as experimental animals, and 30 mg/kg KA was administered intraperitoneally. To confirm the KA-induced neuronal damage in the hippocampal CA3 region, Fluoro-Jade B histofluorescence staining was performed. In addition, the time-dependent change of Nurr1 protein expression was also examined using immunohistochemistry and western blot analysis. Results: Marked neuronal damage was observed in the hippocampal CA3 region at 24 hr after KA injection. In addition, both Nurr1 immunoreactivity and protein level were significantly increased at 6 hr and 12 hr after KA injection, and then decreased at 24 hr after KA injection. Conclusion: This result indicates that KA-induced alteration of Nurr1 protein expression may be associated with the neuronal degeneration in the hippocampal CA3 region after KA injection.

13.
Polymers (Basel) ; 12(5)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365512

RESUMO

p66shc, a member of the shc adaptor protein family, has been shown to participate in regulation of mitochondrial homeostasis, apoptosis, and autophagosome formation. The present study was performed to investigate whether p66shc siRNA-encapsulated poly(d,l-lactic-co-glycolic acid) nanoparticles (p66shc siRNA-PLGA NPs) can attenuate spinal nerve ligation (SNL)-induced neuropathic pain in rats. The SNL-induced pain behavior was decreased in the p66shc siRNA-PLGA NP-treated group compared with the scrambled siRNA-PLGA NP-treated group. In the L5 spinal cord of the p66shc siRNA-PLGA NP-treated group, expression levels of phosphorylated p66shc, cleaved caspase-3, p62, and PINK1, as well as microglial activation, were also decreased. In addition, p66shc knockdown using p66shc siRNA reduced the expression levels of cleaved caspase-3, p62, and PINK1, as well as proinflammatory mediators in the H2O2-treated HT22 neuronal cells. These results suggest that downregulation of p66shc expression in the spinal cord using p66shc siRNA-PLGA NPs could reduce the SNL-induced neuropathic pain by attenuating the SNL-induced aberrant autophagic, mitophagic, and neuroinflammatory processes in rats.

14.
Mol Med Rep ; 22(2): 1044-1052, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468005

RESUMO

Monocarboxylate transporter 4 (MCT4) is a high­capacity lactate transporter in cells and the alteration in MCT4 expression harms cellular survival. The present study investigated whether hypothermia affects tumor necrosis factor­α (TNF­α) and MCT4 immunoreactivity in the subfield cornu ammonis 1 (CA1) following cerebral ischemia/reperfusion (IR) in gerbils. Hypothermia was induced for 30 min before and during ischemia. It was found that IR­induced death of pyramidal neurons was markedly augmented and occurred faster under hyperthermia than under normothermia. TNF­α immunoreactivity in the pyramidal cells started to increase at 3 h after IR and peaked at 1 day after IR under normothermia. However, in hyperthermic control and sham operated gerbils, TNF­α immunoreactivity was significantly increased compared with the normothermic gerbils, and IR under hyperthermia caused a more rapid and significant increase in TNF­α immunoreactivity in pyramidal neurons than under normothermia. In addition, in the normothermic gerbils, MCT4 immunoreactivity began to decrease in pyramidal neurons from 3 h after IR and markedly increased at 1 and 2 days after IR. On the other hand, MCT4 immunoreactivity in pyramidal neurons of the hyperthermic gerbils was significantly increased from 3 h after IR, maintained until 1 day after IR and markedly decreased at 2 days after IR. These results indicate that acceleration of IR­induced neuronal death under hyperthermia might be closely associated with early alteration of TNF­α and MCT4 protein expression in the gerbil hippocampus after IR.


Assuntos
Região CA1 Hipocampal/metabolismo , Morte Celular , Hipertermia/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neurônios/metabolismo , Traumatismo por Reperfusão/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Fluoresceínas/química , Gerbillinae , Masculino , Neurônios/citologia , Células Piramidais/metabolismo , Células Piramidais/patologia
15.
Mar Drugs ; 18(4)2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32326571

RESUMO

Laminarin is a polysaccharide isolated from brown algae that has various biological and pharmacological activities, such as antioxidant and anti-inflammatory properties. We recently reported that pretreated laminarin exerted neuroprotection against transient forebrain ischemia/reperfusion (IR) injury when we pretreated with 50 mg/kg of laminarin once a day for seven days in adult gerbils. However, there have been no studies regarding a neuroprotective effect of pretreated laminarin against IR injury in aged animals and its related mechanisms. Therefore, in this study, we intraperitoneally inject laminarin (50 mg/kg) once a day to aged gerbils for seven days before IR (5-min transient ischemia) surgery and examine the neuroprotective effect of laminarin treatment and the mechanisms in the gerbil hippocampus. IR injury in vehicle-treated gerbils causes loss (death) of pyramidal neurons in the hippocampal CA1 field at five days post-IR. Pretreatment with laminarin effectively protects the CA1 pyramidal neurons from IR injury. Regarding the laminarin-treated gerbils, production of superoxide anions, 4-hydroxy-2-nonenal expression and pro-inflammatory cytokines [interleukin(IL)-1ß and tumor necrosis factor-α] expressions are significantly decreased in the CA1 pyramidal neurons after IR. Additionally, laminarin treatment significantly increases expressions of superoxide dismutase and anti-inflammatory cytokines (IL-4 and IL-13) in the CA1 pyramidal neurons before and after IR. Taken together, these findings indicate that laminarin can protect neurons from ischemic brain injury in an aged population by attenuating IR-induced oxidative stress and neuroinflammation.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Glucanos/farmacologia , Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Gerbillinae , Hipocampo/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção , Superóxido Dismutase/metabolismo
16.
J Cell Mol Med ; 24(4): 2688-2700, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31958895

RESUMO

In this study, we investigated the effects and molecular mechanisms of 2-phenylbenzimidazole-5-sulphonic acid (PBSA), an ultraviolet B protecting agent used in sunscreen lotions and moisturizers, on ovarian cancer cell responses and tumour angiogenesis. PBSA treatment markedly blocked mitogen-induced invasion through down-regulation of matrix metalloproteinase (MMP) expression and activity in ovarian cancer SKOV-3 cells. In addition, PBSA inhibited mitogen-induced cell proliferation by suppression of cyclin-dependent kinases (Cdks), but not cyclins, leading to pRb hypophosphorylation and G1 phase cell cycle arrest. These anti-cancer activities of PBSA in ovarian cancer cell invasion and proliferation were mediated by the inhibition of mitogen-activated protein kinase kinase 3/6-p38 mitogen-activated protein kinase (MKK3/6-p38MAPK ) activity and subsequent down-regulation of MMP-2, MMP-9, Cdk4, Cdk2 and integrin ß1, as evidenced by treatment with p38MAPK inhibitor SB203580. Furthermore, PBSA suppressed the expression and secretion of vascular endothelial growth factor in SKOV-3 cells, leading to inhibition of capillary-like tubular structures in vitro and angiogenic sprouting ex vivo. Taken together, our results demonstrate the pharmacological effects and molecular targets of PBSA on modulating ovarian cancer cell responses and tumour angiogenesis, and suggest further evaluation and development of PBSA as a promising chemotherapeutic agent for the treatment of ovarian cancer.


Assuntos
Imidazóis/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/farmacologia , Adipatos/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Fase G1/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Succinatos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Mol Med Rep ; 21(1): 107-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746417

RESUMO

Nuclear receptor related 1 protein (Nurr1), a member of the nuclear receptor 4 family of orphan nuclear receptors, has been reported to display anti­inflammatory properties. The present study investigated the alteration of Nurr1 immunoreactivity in the gerbil hippocampus proper following 5 min of transient global cerebral ischemia. In sham operated gerbils, Nurr1 immunoreactivity was observed in pyramidal neurons in all cornu ammonis 1­3 (CA1­3) subfields of the hippocampus proper. In ischemia­operated gerbils, Nurr1 immunoreactivity was altered in the CA1 subfield. Nurr1 immunoreactivity in CA1 pyramidal neurons gradually decreased until 2 days post­ischemia, and, at 4 days post­ischemia, Nurr1 immunoreactivity was concentrated in CA1 pyramidal neurons. Additionally, Nurr1 immunoreactivity was newly expressed in microglia in the CA1 subfield at 4 days post­ischemia. Conversely, in the CA2/3 subfield, time­dependent alteration of Nurr1 immunoreactivity was not identified at any time following ischemia. These results indicated that the alteration of Nurr1 expression in the CA1 subfield in the hippocampus may be associated with the death of CA1 pyramidal neurons.


Assuntos
Isquemia Encefálica/metabolismo , Região CA1 Hipocampal/metabolismo , Regulação da Expressão Gênica , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Células Piramidais/metabolismo , Animais , Isquemia Encefálica/patologia , Região CA1 Hipocampal/patologia , Gerbillinae , Masculino , Células Piramidais/patologia
18.
Int J Mol Med ; 44(5): 1801-1810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31573045

RESUMO

Hyperpolarization­activated cyclic nucleotide­gated (HCN) channels have been known to participate in the regulation of neuronal excitability, synaptic transmission and long­term potentiation in the hippocampus. The present study investigated transient ischemia­induced changes of HCN1 and HCN2 expressions in the Cornu Ammonis 1 (CA1) subfield of the hippocampus in gerbils subjected to 5 min transient global cerebral ischemia (tgCI). Neuronal death was exhibited in pyramidal neurons of the striatum pyramidale in the CA1 subfield 4 days after tgCI. HCN1 and HCN2 immunoreactivities were demonstrated in intact CA1 pyramidal neurons, and were transiently and markedly increased in the CA pyramidal neurons at 6 h after ischemia. Thereafter, they gradually decreased in a time­dependent manner. A total of 4 days after ischemia, HCN1 and HCN2 immunoreactivities were barely detected in the CA1 pyramidal neurons; however, HCN1 and HCN2 were began to be expressed in pericytes and astrocytes at 4 days after ischemia. The results indicated that HCN1 and HCN2 expression levels were apparently changed in the gerbil hippocampal CA1 subfield following tgCI and suggested that ischemia­induced alterations in HCN1 and HCN2 expression levels may be closely associated with the death of CA1 pyramidal neurons following 5 min of tgCI.


Assuntos
Astrócitos/metabolismo , Região CA1 Hipocampal/metabolismo , Gerbillinae/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Pericitos/metabolismo , Células Piramidais/metabolismo , Animais , Morte Celular/fisiologia , Isquemia/metabolismo , Ataque Isquêmico Transitório/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino
19.
Iran J Basic Med Sci ; 22(8): 963-967, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31579454

RESUMO

Objectives: Populus species have various pharmacological properties, including antioxidant activity. In this study, the effects of Populus tomentiglandulosa extract (PTE) on histopathology and antioxidant enzymes in the rat liver and kidney were examined. Materials and Methods: Sprague-Dawley rats were assigned to three groups; (1) normal diet fed group, (2) ascorbic acid-containing diet-fed group as a positive control, (3) PTE-containing diet-fed group. The histopathology in the rat liver and kidney was examined by hematoxylin and eosin staining. The effect of PTE was examined in the rat liver and kidney by immunohistochemistry for antioxidant enzymes, such as superoxide dismutases (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx). Results: No marked histopathological alterations were observed in the liver and kidney of the PTE-containing diet-fed group. In the liver, the mean numbers of SOD1, SOD2, CAT, and GPx immunoreactive cells were significantly increased in the PTE-containing diet-fed rats, compared with those in the normal- and ascorbic acid-containing diet-fed rats. In the kidney, all SOD1, SOD2, CAT, and GPx immunoreactive structures were significantly increased in the PTE-containing diet-fed group, compared with those in the normal- and ascorbic acid-containing diet-fed groups. Conclusion: Results showed that PTE treatment significantly increased antioxidant enzymes in the rat liver and kidney, and we suggest that PTE might have hepato- and nephro-protective potentials against oxidative stress.

20.
Sci Rep ; 9(1): 13032, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506563

RESUMO

Abnormal activation of cyclin-dependent kinase 5 (Cdk5) is associated with pathophysiological conditions. Ischemic preconditioning (IPC) can provide neuroprotective effects against subsequent lethal ischemic insult. The objective of this study was to determine how Cdk5 and related molecules could affect neuroprotection in the hippocampus of gerbils after with IPC [a 2-min transient cerebral ischemia (TCI)] followed by 5-min subsequent TCI. Hippocampal CA1 pyramidal neurons were dead at 5 days post-TCI. However, treatment with roscovitine (a potent inhibitor of Cdk5) and IPC protected CA1 pyramidal neurons from TCI. Expression levels of Cdk5, p25, phospho (p)-Rb and p-p53 were increased in nuclei of CA1 pyramidal neurons at 1 and 2 days after TCI. However, these expressions were attenuated by roscovitine treatment and IPC. In particular, Cdk5, p-Rb and p-p53 immunoreactivities in their nuclei were decreased. Furthermore, TUNEL-positive CA1 pyramidal neurons were found at 5 days after TCI with increased expression levels of Bax, PUMA, and activated caspase-3. These TUNEL-positive cells and increased molecules were decreased by roscovitine treatment and IPC. Thus, roscovitine treatment and IPC could protect CA1 pyramidal neurons from TCI through down-regulating Cdk5, p25, and p-p53 in their nuclei. These findings indicate that down-regulating Cdk5 might be a key strategy to attenuate p53-dependent apoptosis of CA1 pyramidal neurons following TCI.


Assuntos
Apoptose/genética , Região CA1 Hipocampal/citologia , Quinase 5 Dependente de Ciclina/metabolismo , Ataque Isquêmico Transitório/metabolismo , Células Piramidais/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Quinase 5 Dependente de Ciclina/genética , Ataque Isquêmico Transitório/etiologia , Neuroproteção , Fosforilação , Transporte Proteico , Células Piramidais/efeitos dos fármacos , Proteína do Retinoblastoma/metabolismo , Roscovitina/farmacologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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