RESUMEN

The lateral habenula (LHb) projects to the ventral tegmental area (VTA) and dorsal raphe nuclei (DRN) that deliver dopamine (DA) and serotonin (5-HT) to cortical and limbic regions such as the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). Dysfunctions of VTA-related mesocorticolimbic dopaminergic and DRN-related serotonergic systems contribute to non-motor symptoms in Parkinson's disease (PD). However, how the LHb affects the VTA and DRN in PD remains unclear. Here, we used electrophysiological and neurochemical approaches to explore the effects of LHb lesions on the firing activity of VTA and DRN neurons, as well as the levels of DA and 5-HT in related brain regions in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. We found that compared to sham lesions, lesions of the LHb increased the firing rate of DA neurons in the VTA and 5-HT neurons in the DRN, but decreased the firing rate of GABAergic neurons in the same nucleus. In addition, lesions of the LHb increased the levels of DA and 5-HT in the mPFC, ventral hippocampus and BLA compared to sham lesions. These findings suggest that lesions of the LHb enhance the activity of mesocorticolimbic dopaminergic and serotonergic systems in PD.

Asunto(s)

Dopamina , Neuronas Dopaminérgicas , Núcleo Dorsal del Rafe , Habénula , Ratas Sprague-Dawley , Neuronas Serotoninérgicas , Serotonina , Área Tegmental Ventral , Animales , Área Tegmental Ventral/metabolismo , Habénula/metabolismo , Masculino , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Núcleo Dorsal del Rafe/metabolismo , Neuronas Serotoninérgicas/metabolismo , Neuronas Serotoninérgicas/fisiología , Ratas , Serotonina/metabolismo , Dopamina/metabolismo , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/patología , Corteza Prefrontal/metabolismo , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología

RESUMEN

Purpose: To investigate the inhibition of Streptococcus mutans (S.mutans) and its biofilm by AgBr-nanoparticles (NP) @CTMAB (cetyltrimethyl-ammonium bromide) and evaluate the changes in Polymethyl methacrylate (PMMA)'s surface roughness (Ra), microhardness, and flexural strength during prolonged immersion in AgBr-NP@CTMAB for application in the denture cleaning industry. Patients and Methods: The antibacterial activity of AgBr-NP@CTMAB against S.mutans was measured colony formation assay, OD600 and laser confocal microscopy. Changes in the specimens' values for surface roughness, microhardness, and flexural strength (MPa) were measured after immersion solutions for 180 or 360 days. Results: The AgBr-NP@CTMAB solution exhibited a robust antibacterial effect on planktonic S. mutans, with a minimum bactericidal concentration of 5 µg/mL. The 10 µg/mL AgBr-NP@CTMAB solution efficiently inhibited S. mutans biofilm formation. (2) No significant difference in surface roughness after immersion in AgBr-NP@CTMAB (10 µg/mL and 20 µg/mL) comparing with distilled water (P > 0.05) and Polident had significantly higher than distilled water (P < 0.05). There was a significant decrease in the surface hardness of the PMMA specimens that were immersed in the Polident compared with those in distilled water (P < 0.05). While, no significant differences in surface hardness after immersion in the AgBr-NP@CTMAB (P > 0.05). The result of flexural strength suggested that there was no statistically significant difference (P < 0.05) between AgBr-NP@CTMAB as well as Polident and water. Conclusion: AgBrNP@CTMAB can efficiently inhibit the growth of plankton S.mutans and biofilm formation, without affecting the flexural strength, microhardness, or surface roughness of PMMA. Therefore, AgBrNP@CTMAB holds promise as a new denture cleaning agent.

Asunto(s)

Boratos , Nanopartículas , Polimetil Metacrilato , Sulfatos , Dureza , Resistencia Flexional , Streptococcus mutans , Bases para Dentadura , Agua , Antibacterianos/farmacología , Propiedades de Superficie , Ensayo de Materiales

RESUMEN

Intermittent theta burst stimulation (iTBS), an updated pattern of high-frequency repetitive transcranial magnetic stimulation, is a potential candidate for improving memory. The hippocampus has been shown to be involved in the memory-enhancing effect induced by iTBS. However, it remains largely unknown whether this effect is achieved by regulating hippocampal theta oscillation and neurotransmitters gamma-aminobutyric acid (GABA) and glutamate, which are strongly related to memory. Thus, we investigated the effect of 14 days of iTBS on hippocampus-dependent memory and further explored the roles of hippocampal theta oscillation and neurotransmitters GABA and glutamate in this effect. We found that compared to sham iTBS, real iTBS enhanced hippocampus-dependent memory measured by hole-board test and object place recognition test. Further, real iTBS increased the density of c-Fos positive neurons and normalized power of theta oscillation in the dorsal hippocampus (dHip) compared to sham iTBS. Interestingly, we observed a decrease in the level of extracellular GABA and an increase in the level of extracellular glutamate in the dHip after real iTBS. Our results suggest that long-term iTBS improved hippocampus-dependent memory, which may be attributed to the enhancement of theta oscillation and altered levels of extracellular GABA and glutamate in the dHip.

Asunto(s)

Ritmo Teta , Estimulación Magnética Transcraneal , Ratas , Animales , Estimulación Magnética Transcraneal/métodos , Hipocampo , Ácido Glutámico , Ácido gamma-Aminobutírico

RESUMEN

Depression associated with Parkinson's disease (PD) seriously affects patients, and there is a lack of effective treatments. Transcranial direct current stimulation (tDCS) is increasingly used as a new non-invasive neuromodulation technique in the treatment of neuropsychiatric diseases. However, there is a paucity of research on tDCS for PD-related depression. Our study used PD model rats established with unilateral destruction of the medial forebrain bundle (MFB) to observe the modulatory effects of tDCS acting on the mPFC on depression-like behaviors. We found that tDCS acting on the mPFC improved depression-like behaviors in PD model rats by increasing sucrose intake in sucrose preference test (n = 7-10 rats/group) and shortening immobility time in forced swimming test (n = 7-8 rats/group). Meanwhile, tDCS decreased the expression of c-Fos protein (n = 8-11 rats/group) and the excitation of glutamatergic neurons (n = 6-8 rats/group) in the PrL and LHb of PD model rats. Western blots showed that tDCS decreased the overexpression of serine 845 phosphorylation site of AMPA receptor GluR1 (p-GluR1-S845) in the PrL and LHb of PD model rats (n = 8-11 rats/group), and the overexpression of p-GluR1-S831 in the LHb (n = 8-11 rats/group). The results of this study show that tDCS acting on the mPFC helps to improve PD-related depression, which involves the modulation of excitability and AMPA receptor phosphorylation on the PrL and LHb neurons.

Asunto(s)

Enfermedad de Parkinson , Trastornos Parkinsonianos , Estimulación Transcraneal de Corriente Directa , Humanos , Ratas , Animales , Depresión/terapia , Depresión/metabolismo , Enfermedad de Parkinson/metabolismo , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Trastornos Parkinsonianos/metabolismo , Corteza Prefrontal/metabolismo , Sacarosa/metabolismo

RESUMEN

Background: The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent theta-burst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Objective: Our aim was to explore the effect of acute iTBS on hippocampus-dependent memory in PD and the mechanism underlying it. Methods: Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampus-dependent memory. Results: Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampus-dependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 block-iTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 block-iTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. Conclusion: The results indicate that multiple blocks of iTBS elicit dose and time-dependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus.

RESUMEN

Methamphetamine (METH), a psychostimulant, has the potential to cause neurodegeneration by targeting the cerebrum and cerebellum. It has been suggested that the NLRP3 inflammasome may be responsible for the neurotoxicity caused by METH. However, the role of NLRP3 in METH-induced cerebellar Purkinje cell (PC) degeneration and the underlying mechanism remain elusive. This study aims to determine the consequences of NLRP3 modulation and the underlying mechanism of chronic METH-induced cerebellar PC degeneration. In METH mice models, increased NLRP3 expression, PC degeneration, myelin sheath destruction, axon degeneration, glial cell activation, and motor coordination impairment were observed. Using the NLRP3 inhibitor MCC950, we found that inhibiting NLRP3 alleviated the above-mentioned motor deficits and cerebellar pathologies. Furthermore, decreased mature IL-1ß expression mediated by Caspase 1 in the cerebellum may be associated with the neuroprotective effects of NLRP3 inflammasome inhibition. Collectively, these findings suggest that mature IL-1ß secretion mediated by NLRP3-ASC-Caspase 1 may be a critical step in METH-induced cerebellar degeneration and highlight the neuroprotective properties of inflammasome inhibition in cerebellar degeneration.

RESUMEN

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABAB receptors in the region affects anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to hyperactivity of LHb neurons and decreased the level of extracellular dopamine (DA) in the basolateral amygdala (BLA) compared to sham-lesioned rats. Intra-LHb injection of pre-synaptic GABAB receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABAB receptor antagonist CGP35348 induced anxiety-like responses in both groups. Further, intra-LHb injection of CGP36216 decreased the firing rate of the neurons, and increased the GABA/glutamate ratio in the LHb and release of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 increased the firing rate of the neurons and decreased the GABA/glutamate ratio and release of DA and 5-HT in sham-lesioned and the lesioned rats. However, the doses of the antagonists producing these behavioral effects in the lesioned rats were lower than those in sham-lesioned rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in the lesioned rats. Collectively, these findings suggest that pre-synaptic and post-synaptic GABAB receptors in the LHb are involved in the regulation of anxiety-like behaviors, and degeneration of the nigrostriatal pathway up-regulates function and/or expression of these receptors.

Asunto(s)

Ansiedad/metabolismo , Complejo Nuclear Basolateral/metabolismo , Antagonistas de Receptores de GABA-B/farmacología , Habénula/metabolismo , Trastornos Parkinsonianos/metabolismo , Receptores de GABA-B/metabolismo , Receptores Presinapticos/metabolismo , Animales , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/fisiopatología , Conducta Animal/efectos de los fármacos , Dopamina/metabolismo , Habénula/efectos de los fármacos , Habénula/fisiopatología , Compuestos Organofosforados/farmacología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/psicología , Porción Compacta de la Sustancia Negra , Ácidos Fosfínicos/farmacología , Ratas , Receptores Presinapticos/antagonistas & inhibidores , Serotonina/metabolismo , Regulación hacia Arriba

RESUMEN

OBJECTIVE: To synthesize and determine the antifungal activity of AgBr-nanoparticles (NP) @CTMAB (cetyltrimethyl-ammonium bromide) against Candida albicans (C. albicans) for use in the field of denture cleaning. METHODS: The morphology and structure of AgBr-NP@CTMAB were characterized by IR, UV-Vis, XRD and SEM. The antifungal potential of AgBr-NP@CTMAB against C. albicans was determined by colony formation assay and growth curve analysis. PMMA containing AgBr-NP@CTMAB was prepared, and the long-term antifungal efficacy was analyzed. The effect against C. albicans biofilm was analyzed by SEM and OD600 , and the color changes of the specimens were observed by stereomicroscopy after 1 week of incubation. Cytotoxicity to human oral gingival fibroblasts and oral mucosal epithelial cells was detected by Cell Counting Kit-8 (CCK-8) in vitro. RESULTS: The compound showed a good crystalline phase, the presence of AgBr nanoparticles and the hybridization of CTMAB+ with AgBr-NPs. AgBr-NP@CTMAB showed significant antifungal activity against C. albicans at concentrations of 10 µg/mL and 20 µg/mL. PMMA specimens containing AgBr-NP@CTMAB showed no long-term antifungal effect against C. albicans biofilm. The clearance rate of C. albicans attached to PMMA was 44.73% after soaking in 10 µg/mL AgBr-NP@CTMAB solution for 30 min and 91.35% for 8 h. There was no significant residual cytotoxicity or visual color change after soaking. SIGNIFICANCE: AgBr-NP@CTMAB showed promising potential treatment for denture cleaners.

Asunto(s)

Antifúngicos/síntesis química , Antifúngicos/farmacología , Cetrimonio/química , Nanopartículas/química , Polimetil Metacrilato/química , Antifúngicos/química , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Candida albicans/fisiología , Técnicas de Química Sintética , Humanos , Nanotecnología

RESUMEN

BACKGROUND: The Cathepsins family, including cathepsin B and cathepsin D, potentially affects the entire processes involved in atherosclerosis. Although coronary heart disease (CHD) has been widely studied as the basis of Sudden Cardiac Death (SCD), the relationship between CHD and CTSB/D remains unclear. METHODS: We screened for differentially expressed proteins (DEPs) associated with autophagy by limma package in R. For the genes corresponding to the DEPs after screening, we used various databases to carry out functional enrichment of related DEGs to explore their possible influence on a specific aspect of the disease. Functional enrichment analysis of DEGs was performed by DAVID, Metascape and GSEA. STRING and Cytoscape were obtained the hub genes, the analysis of interaction networks through the GENMANIA and Networkanalyst. Western Blot was used to validate the protein expression level of target genes. TF and miRNA prediction were performed using Networkanalyst and visualized using Cytoscape. RESULTS: The expression levels of members of the cathepsin family were up regulated in CHD tissues compared with the control. GO and KEGG revealed that cathepsin was markedly enriched in endopeptidase activities, immune responses, lysosome pathways, et al. The correlation analysis showed that in patients with CHD, the CTSB/CTSD expression were negatively correlated with ATG4D and BNIP3, but positively with BCL2L1, CAPNS1, and TP53. In the TF-mRNA-miRNA network, has-miR-24-3p and has-miR-128-3p had higher degrees, CTSB/CTSD could be targeted by them. CONCLUSIONS: Our findings elucidated the expression and regulatory role of cathepsins in coronary heart disease induced SCD and might further explore the potential mechanisms of autophagy in CHD.

Asunto(s)

Proteínas Relacionadas con la Autofagia/genética , Autofagia/genética , Catepsina B/genética , Catepsina D/genética , Enfermedad Coronaria/genética , Muerte Súbita , Proteínas Relacionadas con la Autofagia/metabolismo , Catepsina B/metabolismo , Catepsina D/metabolismo , Enfermedad Coronaria/enzimología , Enfermedad Coronaria/patología , Bases de Datos Genéticas , Muerte Súbita/patología , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Mapas de Interacción de Proteínas

RESUMEN

BACKGROUND: The realization of multifunction in one bulk material is fascinating for developing a new generation of devices. Quaternary phosphorus salts were seldom utilized as templates in haloargentate systems, and the hybridization of alkyl(triphenyl)phosphonium with halometallate will be a good strategy for the development of multifunctional material, especially for biological material. METHODS: Under the template of (triphenyl)phosphonium-based quaternary phosphorus salts with different spacer lengths (n=2, 3, 4), three bromoargentate hybrids were constructed via the solution method, ie, (1,2-DBTPP)(Ag2Br4) (1), {(1,3-DBTPP)2(Ag7Br11)]∙CH3CN∙H2O} n (2), and {[(1,4-DBTPP)(Ag5Br7)](CH3CN)2∙H2O} n (3) (1,2-DBTPP2+=ethane-1,2-diylbis (triphenyl)phosphonium, 1,3-DBTPP2+=propane-1,3-diylbis (triphenyl)phosphonium, 1,4-DBTPP2+=butane-1,4-diylbis (triphenyl)phosphonium)). RESULTS: The (Ag7Br11) n 4n- chain in 2 is a new type of 1-D bromoargentate chain constructed from cubane-like Ag4Br4 nodes, AgBr4 tetrahedrons and AgBr3 triangles. Interestingly, by elongating spacer n from 2 to 4, argentophilicity interactions are weakened, and the hydrogen bonds are strengthened. Consequently, their water stabilities and photocurrents are improved, in which the Ag-4d/Br-4p to π* anti-bonding orbital of the quaternary phosphorus transfer is facilitated. Furthermore, the greenish blue emissions can be detected. Finally, high inhabitation rates against Streptococcus mutans and Candida albicans can be observed in 2 and 3. CONCLUSION: In all experiments, by elongating the spacer lengths of quaternary phosphorus salts, multifunctions were integrated in the quaternary phosphorus/bromoargentate hybrids, including greenish blue luminescence, repeatable photocurrent responses and durable antimicrobial activities with enhanced water stability. This work could provide a theoretical guide for the design of new biologically multifunctional materials.

Asunto(s)

Antiinfecciosos/química , Antiinfecciosos/farmacología , Compuestos de Bromina/química , Ácidos Grasos/química , Fósforo/química , Antiinfecciosos/farmacocinética , Compuestos de Bromina/farmacología , Candida albicans/efectos de los fármacos , Cristalografía por Rayos X , Estabilidad de Medicamentos , Ácidos Grasos/farmacología , Luminiscencia , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Procesos Fotoquímicos , Streptococcus mutans/efectos de los fármacos , Agua/química

RESUMEN

Although multiple studies report that unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induce depressive-like behaviors and hyperactivity of the lateral habenula (LHb), effects of dopamine (DA) D4 receptors in the LHb on depressive-like behaviors are unclear. Here we found that intra-LHb injection of the different doses of D4 receptor agonist A412997 and antagonist L741742 produced the different behavioral responses in SNc sham-lesioned rats, and only the high doses of A412997 and L741742 increased the expression of depressive-like behaviors or produced antidepressant-like effects in SNc-lesioned rats. The low doses of A412997 and L741742 altered the firing rate of LHb neurons and release of DA, GABA and glutamate in the LHb via the GABAergic rostromedial tegmental nucleus (RMTg) in SNc sham-lesioned rats, but not in SNc-lesioned rats. The high doses of A412997 and L741742 also altered the firing rate and release of the transmitters in both SNc sham-lesioned and SNc-lesioned rats, whereas these effects were not involved in the RMTg. Lesions of the SNc shortened the duration of significant effects on the firing rate and release of the transmitters induced by the high doses of A412997 and L741742. These findings suggest that D4 receptors in the LHb are involved in depression-like behaviors via the pre- and post-synaptic mechanisms and depletion of DA decreases the function and/or the expression of both pre- and post-synaptic D4 receptors. This study also points to the importance of the pre-synaptic D4 receptors in the regulation of Parkinson's disease-related depression.

Asunto(s)

Depresión/metabolismo , Habénula/metabolismo , Trastornos Parkinsonianos/metabolismo , Terminales Presinápticos/metabolismo , Receptores de Dopamina D4/metabolismo , Animales , Depresión/inducido químicamente , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Habénula/efectos de los fármacos , Ácido Iboténico/toxicidad , Masculino , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inhibidores

RESUMEN

Working memory impairment is a common symptom occurred in Parkinson's disease (PD). The medial septum-diagonal band (MS-DB) complex and 5-HT6 receptor are involved in modulation of cognition. However, their roles in working memory in PD are still unknown. Here, we used behavioral, neurochemical and immunohistochemical approaches to assess the role of MS-DB 5-HT6 receptor in working memory in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. Intra-MS-DB injection of 5-HT6 receptor agonist WAY208466 (3, 6 and 12 µg/rat) enhanced working memory and increased dopamine (DA) and noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) and hippocampus in sham and 6-OHDA-lesioned rats. The dose that produced significant effect on working memory in 6-OHDA-lesioned rats was lower than that in sham rats, indicating hypersensitivity of 5-HT6 receptor after lesioning. Intra-MS-DB injection of 5-HT6 receptor antagonist SB258585 (2, 4 and 8 µg/rat) alleviated working memory deficits and increased DA level in the mPFC and hippocampus and NA level in the mPFC in 6-OHDA-lesioned rats while having no effect in sham rats, suggesting that SB258585 did not change normal cognitive status. These results suggest that activation and blockade of MS-DB 5-HT6 receptor recovered working memory in 6-OHDA-lesioned rats, which is probably related to changes in monoamine levels in the mPFC and hippocampus.

Asunto(s)

Banda Diagonal de Broca/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Enfermedad de Parkinson Secundaria/metabolismo , Receptores de Serotonina/metabolismo , Núcleos Septales/efectos de los fármacos , Animales , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Metilaminas/farmacología , Norepinefrina/metabolismo , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley

RESUMEN

Coronavirus disease 2019 (COVID-19) has widely spread all over the world and the numbers of patients and deaths are increasing. According to the epidemiology, virology, and clinical practice, there are varying degrees of changes in patients, involving the human body structure and function and the activity and participation. Based on the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) and its biopsychosocial model of functioning, we use the WHO Family of International Classifications (WHO-FICs) framework to form an expert consensus on the COVID-19 rehabilitation program, focusing on the diagnosis and evaluation of disease and functioning, and service delivery of rehabilitation, and to establish a standard rehabilitation framework, terminology system, and evaluation and intervention systems based the WHO-FICs.

RESUMEN

Although the lateral habenula (LHb) is involved in the regulation of multiple brain functions and this region expresses abundant M-type potassium channel (M-channel) subunits Kv7.2 and Kv7.3, the role of M-channels in regulating working memory is unclear, particularly in Parkinson's disease (PD). Here we tested the effects of activation and blockade of LHb M-channels on working memory by the T-maze rewarded alternation test in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc). The SNc lesion induced working memory impairment, increased the firing rate of LHb neurons, decreased dopamine (DA) level in the ventral medial prefrontal cortex (vmPFC) and reduced the expression of Kv7.2 subunit in the LHb. Intra-LHb injection of M-channel activator retigabine induced enhancement of working memory in SNc sham-lesioned and SNc-lesioned rats; conversely, the injection of M-channel blocker XE-991 impaired working memory in the two groups of rats. However, doses producing significant effects in SNc-lesioned rats were higher than those in SNc sham-lesioned rats. Further, intra-LHb injection of retigabine decreased the firing rate of LHb neurons and increased release of DA and serotonin (5-HT) in the vmPFC, while XE-991 increased the firing rate and decreased DA and 5-HT release in the two groups of rats. Compared with SNc sham-lesioned rats, the duration of M-channel activation and blockade action on the firing rate of the neurons and release of DA and 5-HT was significantly shortened in SNc-lesioned rats, which was consistent with reduced expression of Kv7.2 subunit in the LHb after lesioning the SNc. Collectively, these findings suggest involvement of LHb Kv7.2 subunit-containing M-channels in working memory impairment in SNc-lesioned rats, and that enhanced or impaired working memory after activation or blockade of M-channels in the LHb is related to the changes in the firing activity of LHb neurons and DA and 5-HT release in the vmPFC.

Asunto(s)

Habénula/metabolismo , Canal de Potasio KCNQ2/biosíntesis , Memoria a Corto Plazo/fisiología , Trastornos Parkinsonianos/metabolismo , Animales , Habénula/efectos de los fármacos , Canal de Potasio KCNQ2/agonistas , Canal de Potasio KCNQ2/antagonistas & inhibidores , Masculino , Moduladores del Transporte de Membrana/farmacología , Memoria a Corto Plazo/efectos de los fármacos , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Bloqueadores de los Canales de Potasio/farmacología , Subunidades de Proteína/biosíntesis , Ratas , Ratas Sprague-Dawley

RESUMEN

Acute spinal cord injury (SCI) has a high rate of disability and mortality. Although secondary SCI results in local tissue hypoxia and the release of inflammatory mediators, it is both controllable and reversible. Therefore, timely rehabilitation treatment is beneficial for the partial recovery of patients with SCI. The present study aimed to investigate the use of methylprednisolone combined with high-frequency electrotherapy as a method of rehabilitation treatment in rats with SCI. The rat SCI model was prepared using the modified Allen's method with the animals randomly divided into the following 4 groups (n=10 for each group): SCI; methylprednisolone (300 mg/kg); high-frequency electrotherapy; and combination treatment with electrotherapy combined with methylprednisolone (300 mg/kg). The Basso, Beattie and Bresnahan (BBB) score, somatosensory evoked potential (SEP) and motor evoked potential (MEP) were used to assess spinal function. Brain-derived neurotrophic factor (BDNF) and NF-κB expression levels were detected using reverse transcription-quantitative PCR and western blotting. Tumor necrosis factor (TNF)-α and IL-2 expression levels were determined by ELISA, and caspase 3 activity was also assessed. In all treatment groups, BDNF mRNA and protein expression levels were significantly increased, whilst those of NF-κB were reduced. Additionally, an elevated BBB score, improved SEPs and MEPs, inhibited caspase 3 activity and downregulated TNF-α and IL-2 expression levels were observed, compared with the SCI group (P<0.05). However, the combination group exhibited more significant effects on SCI. In conclusion, methylprednisolone combined with high frequency electrotherapy may improve the symptoms of SCI by increasing the expression level of BDNF, reducing that of NF-κB, and suppressing the secretion of inflammatory factors.

RESUMEN

At present, whether α2-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related anxiety is unclear. We examined the effects of PrL α2-adrenoceptors on anxiety-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Compared to the sham operation, the lesion induced anxiety-like responses as measured by the open field test and elevated plus-maze test. Intra-PrL injection of the α2-adrenoceptor agonist clonidine (1.25, 2.5 or 5 µg/rat) produced anxiolytic effects in sham-operated and lesioned rats. Furthermore, intra-PrL injection of the α2-adrenoceptor antagonist idazoxan (1, 2 or 4 µg/rat) induced anxiogenic effects in two groups of rats. The effective doses produced by clonidine and idazoxan in lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of clonidine (5 µg/rat) or idazoxan (4 µg/rat) decreased or increased dopamine (DA) and noradrenaline (NA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) and amygdala in sham-operated and lesioned rats, respectively. These results suggest that α2-adrenoceptors in the PrL are involved in the regulation of anxiety-like behaviors, which is attributable to changes in DA, NA and 5-HT levels in the mPFC and amygdala after activation and blockade of α2-adrenoceptors.

Asunto(s)

Ansiedad/metabolismo , Sistema Límbico/metabolismo , Trastornos Parkinsonianos/metabolismo , Corteza Prefrontal/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/fisiopatología , Aminas Biogénicas/metabolismo , Clonidina/farmacología , Idazoxan/farmacología , Sistema Límbico/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Corteza Prefrontal/efectos de los fármacos , Ratas Sprague-Dawley

RESUMEN

After spinal cord injury, microglial cells are activated and converted to an M1 phenotype. Emerging evidence supports the hypothesis that glucose reprogramming accompanies microglial activation. What contributes to the activation of microglia and glucose reprogramming, however, remains unclear. In the current study, we investigated the role and underlying mechanism of a-synuclein in regulating the aerobic glycolysis in microglia. We found that a-synuclein contributed to the reprogramming of glucose metabolism in microglia by promoting glycolysis and inhibiting mitochondrial biogenesis and oxidative phosphorylation. Further studies demonstrated that pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, mediated glucose reprogramming regulated by a-synuclein. A co-immunoprecipitation assay and Western blot assay demonstrated that a-synuclein interacted with PKM2. Further studies demonstrated that knockdown of PKM2 in a-synuclein-exposed microglia markedly reduced glycolysis and lactate production. Additionally, a-synuclein exposure promoted migration abilities in glucose-cultured microglia, whereas migration ability was suppressed in PKM2 knockdown microglia. Additionally, the PKM2 activator TEPP-46 promoted migration ability in a-synuclein-treated microglia, compared to treatment with a-synuclein alone. In conclusion, we demonstrate a PKM2-dependent glycolysis of a-synuclein in microglial.

Asunto(s)

Movimiento Celular/efectos de los fármacos , Glucólisis/efectos de los fármacos , Microglía/citología , Microglía/efectos de los fármacos , Piruvato Quinasa/metabolismo , alfa-Sinucleína/farmacología , Animales , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/genética , Humanos , Microglía/metabolismo , Piruvato Quinasa/deficiencia , Piruvato Quinasa/genética , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

Microglial cell migration and infiltration plays a critical role in spinal cord injury after thoracoabdominal aortic surgery. In our previous study, α-synuclein, a presynaptic protein was shown to be released from injured neurons and cause microglial cell activation. Here, we aimed to explore the effect of α-synuclein on microglial cell migration. Primary microglial cells were isolated from Sprague-Dawley rats and then exposed different doses (0.2, 0.4, and 0.6 µM) of α-synuclein oligomers. The mRNA and protein levels of HIF-1α were then analyzed by qRT-PCR and Western blot. Cell migration was examined by a 96-well Boyden chamber. Moreover, toll-like receptor (TLR) 2-expression as well as TLR7/8-expression was inhibited by specific siRNA transfection. HIF-1α was overexpressed by Ad-HIF-1α transfection. In the results, α-synuclein was found to stimulate HIF-1α accumulation in microglial cells in a dose-dependent manner. Silencing HIF-1α expression dampened α-synuclein induced microglial cell migration. Furthermore, blockade of TLR7/8 expression but not TLR2 expression reduced HIF-1α accumulation in microglial cells. In addition, overexpressed HIF-1α, along with Src, prompted caveolin-1 expression and phosphorylation, as well as migration in microglial cells. Α-synuclein acts via TLR7/8 and enhances HIF-1α expression, which might play a regulatory role in microglial cell migration. © 2017 Wiley Periodicals, Inc.

Asunto(s)

Movimiento Celular/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Microglía/metabolismo , alfa-Sinucleína/farmacología , Animales , Aorta/cirugía , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Masculino , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/etiología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Procedimientos Quirúrgicos Vasculares/efectos adversos

RESUMEN

The lateral habenula (LHb) plays an important role in the regulation of depression. At present, it is not clear whether GABAA receptor-mediated inhibitory transmission in the LHb is involved in Parkinson's disease (PD)-associated depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to sham-operated rats, which attribute to depletion of dopamine, and decreased synthesis and release of GABA and increased release of glutamate in the LHb. Intra-LHb injection of GABAA receptor agonist muscimol produced antidepressant-like effects, while the injection of GABAA receptor antagonist picrotoxin induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. However, the doses producing these behavioral effects in the lesioned rats were lower than those in sham-operated rats. Intra-LHb injection of muscimol decreased the firing rate of LHb neurons and increased the medial prefrontal cortex serotonin (5-HT) release; conversely, picrotoxin increased the firing rate of the neurons and decreased 5-HT release in two groups of rats. Compared to sham-operated rats, the duration of muscimol and picrotoxin action on the firing rate of the neurons and 5-HT release was prolonged in the lesioned rats. These changes in the lesioned rats were associated with up-regulation of the expression of α1 subunit-containing GABAA receptors and reduction of GABA release in the LHb. Collectively, our findings suggest that degeneration of the nigrostriatal pathway impairs GABAA receptor-mediated inhibitory transmission in the LHb, and the transmission is important for regulating PD-associated depression.

Asunto(s)

Depresión/metabolismo , Habénula/metabolismo , Inhibición Neural/fisiología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/psicología , Receptores de GABA-A/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Apomorfina/farmacología , Depresión/patología , Agonistas de Dopamina/farmacología , Antagonistas del GABA/farmacología , Agonistas de Receptores de GABA-A/farmacología , Habénula/efectos de los fármacos , Habénula/patología , Masculino , Muscimol/farmacología , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Oxidopamina , Trastornos Parkinsonianos/patología , Picrotoxina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Ratas Sprague-Dawley , Serotonina/metabolismo

RESUMEN

The aim of the present study was to investigate the age­related alterations in hypertensive brain damage in the hippocampi of spontaneously hypertensive rats (SHR) and the underlying mechanisms. Aging resulted in a significant increase in the number of activated astrocytes and apoptotic cells in the SHR group, which was accompanied by increased expression of oxidative stress markers (iNOS and gp47phox) and apoptotic regulatory proteins (Bax and caspase­3). In addition, the expression of PPAR­Î³ and Bcl­2 were progressively reduced with increasing age in the SHR group. The 32 and 64­week­old SHRs exhibited significantly increased numbers of apoptotic cells, oxidative stress markers and pro­apoptotic proteins compared with age­matched WKY rats, which was accompanied by reduced expression of PPAR­Î³. Compared with the 16 and 32­week­old WKY group, the 64­week­old WKY rats exhibited increased oxidative stress and pro­apoptotic markers, and increased levels apoptotic cells. In conclusion, the present study indicated that both aging and hypertension enhanced brain damage and oxidative stress injury in the hippocampi of SHRs, indicated by an increased presence of apoptotic cells and astrocytes. In addition, reduced expression of PPAR­Î³ may contribute to the age­related brain damage in SHRs.

Asunto(s)

Envejecimiento , Hipocampo/patología , Hipertensión/patología , Animales , Apoptosis , Caspasa 3/metabolismo , Hipocampo/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Proteína X Asociada a bcl-2/metabolismo