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1.
Br J Anaesth ; 123(6): 853-864, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558312

RESUMO

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.


Assuntos
Dopamina/metabolismo , Variação Genética/genética , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Dor Crônica/genética , Dor Crônica/metabolismo , Dopamina/genética , Humanos , Transmissão Sináptica/genética
2.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480244

RESUMO

Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.


Assuntos
Fluoxetina/farmacologia , Ácido Glutâmico/metabolismo , Proteínas SNARE/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Canais de Cálcio/metabolismo , Exocitose/efeitos dos fármacos , Feminino , Humanos , Modelos Neurológicos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/fisiologia , Proteína Quinase C/metabolismo , Ratos Wistar
3.
Life Sci ; 235: 116819, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473194

RESUMO

AIMS: Traumatic brain injury (TBI) not only induces physiological disabilities but also leads to cognitive impairment. However, no effective therapeutic approach for TBI-related memory decline exists. In this study, we treated TBI mice with cinnamic acid (CNA) to detect whether CNA is able to rescue the memory deficits induced by TBI and to explore the potential mechanisms. MAIN METHODS: Mice were divided into the following groups: the sham group, the TBI group, the TBI + CNA group and the CNA group. Basic physiological parameters, neurological severity score and brain water content were analyzed. The Morris water maze and inhibitory avoidance step-down task were used to determine learning and memory. Golgi staining was used to measure alterations in dendritic spines. Western blot analysis and a commercial kit were used to detect the content and activity of HDAC2. qPCR was used to detect the relative level of miR-455. KEY FINDINGS: CNA did not affect physiological function but effectively restored neurological function and brain edema. CNA alleviated the memory impairments induced by TBI in both the Morris water maze and step-down task. CNA also recovered abnormalities in the synapses of TBI mice by suppressing the activity of HDAC2. Furthermore, CNA did not alter HDAC mRNA because it promoted the expression of miR-455-3p, a miRNA that regulates HDAC2 at the posttranscriptional level. SIGNIFICANCE: The application of CNA effectively treats TBI-induced memory deficits by increasing miR-455-3p and by inhibiting HDAC2.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Cinamatos/farmacologia , Histona Desacetilase 2/metabolismo , Transtornos da Memória/prevenção & controle , MicroRNAs/genética , Transmissão Sináptica/efeitos dos fármacos , Animais , Histona Desacetilase 2/genética , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
4.
Gen Physiol Biophys ; 38(5): 399-406, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31411570

RESUMO

The substantia gelatinosa of the trigeminal subnucleus caudalis has been considered to be an essential location for the transference of orofacial sensory signals. The co-localization of inhibitory and excitatory neurotransmitters in the same substantia gelatinosa (SG) neurons has demonstrated their essential part in the modification of nociceptive transmission. Zn2+ is particularly numerous in the mammalian central nervous system. There are proofs demonstrating the role of Zn2+ in the modulation of voltage- and ligand-gated ion channels. However, little is known about what roles Zn2+ may play in the modulation of signal transmission in the SG neurons of the trigeminal subnucleus caudalis (Vc). Therefore, in this study, we used the whole-cell patch clamp technique to find out the effect of Zn2+ on the responses of three main neurotransmitters (glycine, GABA, and glutamate) on SG neurons of the Vc in mice. We have proved that Zn2+ induces a big potentiation of glycine receptor-mediated response but attenuates GABA- and glutamate-induced responses at micromolar concentrations, however, enhances glutamate-induced response at nanomolar concentration. Taken together, these data demonstrated that Zn2+ can modulate glycine, GABA and glutamate-mediated actions on the SG neurons of the Vc and support an important mechanism in spinal sensory information signaling.


Assuntos
Neurônios/efeitos dos fármacos , Substância Gelatinosa/citologia , Transmissão Sináptica/efeitos dos fármacos , Zinco/farmacologia , Animais , Ácido Glutâmico/metabolismo , Glicina/metabolismo , Camundongos , Neurotransmissores/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Receptores da Glicina/metabolismo , Ácido gama-Aminobutírico/metabolismo
5.
PLoS Comput Biol ; 15(8): e1006938, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31469828

RESUMO

The mechanism(s) of action of most commonly used pharmacological blockers of voltage-gated ion channels are well understood; however, this knowledge is rarely considered when interpreting experimental data. Effects of blockade are often assumed to be equivalent, regardless of the mechanism of the blocker involved. Using computer simulations, we demonstrate that this assumption may not always be correct. We simulate the blockade of a persistent sodium current (INaP), proposed to underlie rhythm generation in pre-Bötzinger complex (pre-BötC) respiratory neurons, via two distinct pharmacological mechanisms: (1) pore obstruction mediated by tetrodotoxin and (2) altered inactivation dynamics mediated by riluzole. The reported effects of experimental application of tetrodotoxin and riluzole in respiratory circuits are diverse and seemingly contradictory and have led to considerable debate within the field as to the specific role of INaP in respiratory circuits. The results of our simulations match a wide array of experimental data spanning from the level of isolated pre-BötC neurons to the level of the intact respiratory network and also generate a series of experimentally testable predictions. Specifically, in this study we: (1) provide a mechanistic explanation for seemingly contradictory experimental results from in vitro studies of INaP block, (2) show that the effects of INaP block in in vitro preparations are not necessarily equivalent to those in more intact preparations, (3) demonstrate and explain why riluzole application may fail to effectively block INaP in the intact respiratory network, and (4) derive the prediction that effective block of INaP by low concentration tetrodotoxin will stop respiratory rhythm generation in the intact respiratory network. These simulations support a critical role for INaP in respiratory rhythmogenesis in vivo and illustrate the importance of considering mechanism when interpreting and simulating data relating to pharmacological blockade.


Assuntos
Modelos Neurológicos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/inervação , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Biologia Computacional , Simulação por Computador , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Centro Respiratório/efeitos dos fármacos , Centro Respiratório/fisiologia , Sistema Respiratório/metabolismo , Riluzol/farmacologia , Canais de Sódio/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetrodotoxina/farmacologia
6.
Biol Pharm Bull ; 42(8): 1433-1436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366880

RESUMO

The medial prefrontal cortex (mPFC) plays critical roles in the development of cocaine addiction. Numerous studies have reported about the effects of cocaine on neuronal and synaptic activities in the nucleus accumbens and ventral tegmental area, which are brain regions associated with cocaine addiction; however, a limited number of studies have reported the effect of cocaine on mPFC neuronal activity. In this study, using whole-cell patch-clamp recordings in brain slices, we present that under the condition where synaptic transmission is enhanced by increasing extracellular K+ concentration, cocaine significantly reduced the frequency but not amplitude of spontaneous excitatory postsynaptic currents. These findings suggest that cocaine exposure could be a trigger to induce hypofrontality, which is related to the compulsive craving for cocaine use.


Assuntos
Cocaína/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Feminino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/efeitos dos fármacos
7.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324059

RESUMO

Anti-inflammatory cytokines are known to exert neuroprotective action ameliorating aberrant neuronal network activity associated with inflammatory responses. Yet, it is still not fully understood if anti-inflammatory cytokines play a significant role in the regulation of synaptic activity under normal conditions. Thus, the aim of our study was to investigate the effect of Interleukin-10 (IL-10) on neuronal synaptic transmission and plasticity. For this we tested the effect of IL-10 on miniature excitatory postsynaptic currents (mEPSC) and intracellular Ca2+ responses using whole-cell patch clamp and fluorescence microscopy in 13-15 DIV primary hippocampal neuroglial culture. We found that IL-10 significantly potentiated basal glutamatergic excitatory synaptic transmission within 15 min after application. Obtained results revealed a presynaptic nature of the effect, as IL-10 in a dose-dependent manner significantly increased the frequency but not the amplitude of mEPSC. Further, we tested the effect of IL-10 on mEPSC in a model of homeostatic synaptic plasticity (HSP) induced by treatment of primary hippocampal culture with 1 µM of tetrodotoxin (TTX) for a 24 h. It was found that 15 min application of IL-10 at established HSP resulted in enhanced mEPSC frequency, thus partially compensating for a decrease in the mEPSC frequency associated with TTX-induced HSP. Next, we studied if IL-10 can influence induction of HSP. We found that co-incubation of IL-10 with 1 µM of TTX for 24 h induced synaptic scaling, significantly increasing the amplitude of mEPSC and Ca2+ responses to application of the AMPA agonist, 5-Fluorowillardiine, thus facilitating a compensatory postsynaptic mechanism at HSP condition. Our results indicate that IL-10 potentiates synaptic activity in a dose- and time-dependent manner exerting both presynaptic (short-term exposure) and postsynaptic (long-term exposure) action. Obtained results demonstrate involvement of IL-10 in the regulation of basal glutamatergic synaptic transmission and plasticity at normal conditions.


Assuntos
Hipocampo/citologia , Interleucina-10/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Células Cultivadas , Microscopia de Fluorescência , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Patch-Clamp , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tetrodotoxina/farmacologia
8.
Biomed Res Int ; 2019: 2389485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346513

RESUMO

Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.


Assuntos
Proteínas de Transporte/genética , Coma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Receptor A1 de Adenosina/genética , Adenosina/genética , Adenosina/metabolismo , Animais , Coma/induzido quimicamente , Coma/genética , Coma/patologia , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Receptores de Orexina/genética , Orexinas/genética , Orexinas/metabolismo , Ratos , Reflexo de Endireitamento/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Vigília/efeitos dos fármacos
9.
Br J Anaesth ; 123(3): 335-349, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303268

RESUMO

Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Dor Crônica/tratamento farmacológico , Lidocaína/farmacologia , Terapia de Alvo Molecular/métodos , Dor Aguda/metabolismo , Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Crônica/metabolismo , Humanos , Canais Iônicos/efeitos dos fármacos , Lidocaína/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos
10.
Neurochem Res ; 44(9): 2068-2080, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317507

RESUMO

The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in pain chronification, and glutamatergic neurotransmission may be involved in this process. Thus, the aim of the present work was to investigate the participation of the prelimbic (PrL) area of the mPFC in neuropathic pain as well as the role of N-methyl D-aspartate (NMDA) glutamate receptors in neuropathic pain induced by a modified sciatic nerve chronic constriction injury (CCI) protocol in Wistar rats. Neural inputs to the PrL cortex were inactivated by intracortical treatment with the synapse blocker cobalt chloride (CoCl2, 1.0 mM/200 nL) 7, 14, 21, or 28 days after the CCI or sham procedure. The glutamatergic agonist NMDA (0.25, 1 or 4 nmol) or the selective NMDA receptor antagonist LY235959 (2, 4 or 8 nmol) was microinjected into the PrL cortex 21 days after surgery. CoCl2 administration in the PrL cortex decreased allodynia 21 and 28 days after CCI. NMDA at 1 and 4 nmol increased allodynia, whereas LY235959 decreased mechanical allodynia at the highest dose (8 nmol) microinjected into the PrL cortex. These findings suggest that NMDA receptors in the PrL cortex participate in enhancing the late phase of mechanical allodynia after NMDA-induced increases and LY235959-induced decreases in allodynia 21 days after CCI. The glutamatergic system potentiates chronic neuropathic pain by NMDA receptor activation in the PrL cortex. Mechanism of neuropathic pain. The infusion of CoCl2, a synapse activity blocker, into the prelimbic (PrL) division of the medial prefrontal cortex (mPFC) decreased the severity of mechanical allodynia, showing the late participation of the limbic cortex. The glutamatergic system potentiates chronic neuropathic pain via NMDA receptor activation in the PrL cortex.


Assuntos
Neuralgia/metabolismo , Nervos Periféricos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cobalto/farmacologia , Hiperalgesia/tratamento farmacológico , Isoquinolinas/farmacologia , Masculino , N-Metilaspartato/farmacologia , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos
11.
Front Neural Circuits ; 13: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164809

RESUMO

The sole output of the retina to the brain is a signal that results from the integration of excitatory and inhibitory synaptic inputs at the level of retinal ganglion cells (RGCs). Endogenous cannabinoids (eCBs) are found throughout the central nervous system where they modulate synaptic excitability. Cannabinoid receptors and their ligands have been localized to most retinal neurons in mammals, yet their impact on retinal processing is not well known. Here, we set out to investigate the role of the cannabinoid system in retinal signaling using electrophysiological recordings from ON-sustained (ON-S) RGCs that displayed morphological and physiological signatures of ON alpha RGCs in dark adapted mouse retina. We studied the effect of the cannabinoid agonist WIN55212-2 and the inverse agonist AM251 on the spatial tuning of ON-S RGCs. WIN55212-2 significantly reduced their spontaneous spiking activity and responses to optimal spot size as well as altered their spatial tuning by reducing light driven excitatory and inhibitory inputs to RGCs. AM251 produced the opposite effect, increasing spontaneous spiking activity and peak response as well as increasing inhibitory and excitatory inputs. In addition, AM251 sharpened the spatial tuning of ON-S RGCs by increasing the inhibitory effect of the surround. These results demonstrate the presence of a functional cannabinergic system in the retina as well as sensitivity of ON-RGCs to cannabinoids. These results reveal a neuromodulatory system that can regulate the sensitivity and excitability of retinal synapses in a dynamic, activity dependent manner and that endocannabinoids may play a significant role in retinal processing.


Assuntos
Canabinoides/metabolismo , Potenciais Evocados Visuais/fisiologia , Células Ganglionares da Retina/metabolismo , Transmissão Sináptica/fisiologia , Animais , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Potenciais Evocados Visuais/efeitos dos fármacos , Luz , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
12.
Psychopharmacology (Berl) ; 236(11): 3257-3270, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31165913

RESUMO

RATIONALE: While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse cognitive effects is poorly understood. The cannabinoid 1 receptor modulates memory performance via intracellular and extracellular mechanisms that alter synaptic transmission and plasticity. While previous literature has consistently shown that chronic cannabis users exhibit marked cognitive impairments, mixed findings have been reported in the context of placebo-controlled experimental trials. It is therefore unclear whether these compounds inherently alter cognitive processes or whether individuals who are genetically predisposed to use cannabis may have underlying cognitive deficits. OBJECTIVE: We conducted a meta-analysis to investigate the effects of full and partial cannabinoid 1 receptor (CB1R) agonists, antagonists, and negative allosteric modulators on non-spatial and spatial memory. METHODS: In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining the effects of CB1R agonists, antagonists, and negative allosteric modulators on memory performance. RESULTS: We systematically reviewed 195 studies investigating the effects of cannabinoid compounds on memory. In humans (N = 35 studies, comprising N = 782 subjects), delta-9-tetrahydrocannabinol (THC) (1.5-5 mg/kg) relative to placebo impaired performance on non-spatial memory tests, whereas only high THC doses (67 mg/kg) impaired spatial memory. Similarly, THC (0.2-4 mg/kg) significantly impaired visuospatial memory in monkeys and non-human primates (N = 8 studies, comprising N = 71 subjects). However, acute THC (0.002-10 mg/kg) had no effect on non-spatial (N = 6 studies, comprising 117 subjects; g = 1.72, 95% confidence interval (CI) - 0.18 to 3.63, p = 0.08) or spatial memory (9 studies, comprising 206 subjects; g = 0.75, 95% confidence interval (CI) - 1.09 to 2.58, p = 0.43). However, acute, full CB1R agonists significantly impaired non-spatial memory (N = 23 studies, 519 subjects; g = - 1.39, 95% CI - 2.72 to - 0.06, p = 0.03). By contrast, the chronic administration of CB1R agonists had no effect on non-spatial memory (N = 5 studies, comprising 146 subjects; g = - 0.05, 95% confidence interval (CI) - 1.32 to 1.22, p = 0.94). Moreover, the acute administration of CB1R antagonists had no effect on non-spatial memory in rodents (N = 9 studies, N = 149 subjects; g = 0.40, 95% CI - 0.11 to 0.92, p = 0.12). CONCLUSIONS: The acute administration of THC, partial CB1R agonist, significantly impaired non-spatial memory in humans, monkeys, and non-human primates but not rodents. However, full CB1R agonists significantly impaired non-spatial memory in a dose-dependent manner but CB1R antagonists had no effect on non-spatial memory in rodents. Moreover, chronic THC administration did not significantly impair spatial or non-spatial memory in rodents, and there is inconclusive evidence on this in humans. Our findings highlight species differences in the effects of cannabinoid compounds on memory.


Assuntos
Cognição/efeitos dos fármacos , Cognição/fisiologia , Dronabinol/farmacologia , Memória/efeitos dos fármacos , Memória/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Animais , Canabinoides/efeitos adversos , Canabinoides/farmacologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Dronabinol/efeitos adversos , Humanos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Especificidade da Espécie , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
13.
Eur J Pharmacol ; 858: 172496, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31242440

RESUMO

A natural monoterpene alkaloid incarvillateine isolated from the plant Incarvillea sinensis is known to relieve inflammatory and neuropathic pain. However, the molecular target for the action of incarvillateine remains elusive. Here, we report that incarvillateine exacerbates epileptic seizures by inhibiting subtypes of γ-Aminobutyric acid type A (GABAA) receptors. Two-electrode voltage clamp recordings of α1ß3γ2, α2ß3γ2, α3ß3γ2 and α5ß3γ2 subtypes expressed in Xenopus oocytes revealed that incarvillateine inhibited the GABAA currents with IC50 of 25.1 µM, 43.1 µM, 105.1 µM and 93.7 µM, respectively. Whole-cell patch clamp recordings of hippocampal slices confirmed that incarvillateine inhibited spontaneous inhibitory postsynaptic currents (IPSCs), and miniature IPSCs and tonic currents. Moreover, inhibition of GABAA currents and spontaneous IPSCs by incarvillateine persisted even in the presence of blockers of adenosine receptors. In addition, incarvillateine enhanced epileptic discharges induced by Mg2+-free artificial cerebrospinal fluid (ACSF) in hippocampal slices. Furthermore, intracerebral ventricular injections of incarvillateine increased the severity of seizures induced by kainic acid in a dose-dependent manner. Taken together, our data demonstrate that incarvillateine aggravates seizures by inhibition of GABAA currents and GABAergic synaptic transmissions.


Assuntos
Alcaloides/efeitos adversos , Produtos Biológicos/efeitos adversos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/efeitos adversos , Monoterpenos/efeitos adversos , Receptores de GABA-A/metabolismo , Segurança , Convulsões/fisiopatologia , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Neurotransmissores/metabolismo , Ratos , Convulsões/induzido quimicamente , Convulsões/metabolismo , Transmissão Sináptica/efeitos dos fármacos
14.
BMC Complement Altern Med ; 19(1): 128, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196061

RESUMO

BACKGROUND: Salvia officinalis has been used successfully for the treatment of hot flushes and excessive sweating during menopause. However, modes of actions have not been elucidated conclusively. We explored its pharmacology beyond any hormonal activity with a focus on neurologic impulse transmission. METHODS: A hydroalcoholic, thujone-free extract from freshly harvested Salvia officinalis leaves (A.Vogel Menosan®) was investigated in an acetylcholinesterase enzyme assay and several receptor binding assays (adrenergic alpha 2A, GABA (benzodiazepine site), GABAB; muscarinic M3, µ-opioid, serotonin 5-HT1A, serotonin 5-HT2B, serotonin 5-HT2C and serotonin transporter). The influence of the manufacturing process on additional extracts from different fresh or dry plant parts was studied. RESULTS: The Salvia officinalis extract replaced 50% of specific ligand binding to GABAA and GABAB receptors at an inhibitory concentration (IC50) of 89 and 229 µg/ml, respectively. Strong binding affinity was observed for the adrenergic α2A receptor, µ-opioid receptors, muscarinic M3 receptors, and serotonin 5-HT1A receptors, with IC50 values of 15 µg/ml, 20 µg/ml, 25 µg/ml and 19 µg/ml, respectively. Moderate interference with 5-HT2B, 5-HT2C receptors, and the human serotonin transporter was found, all with IC50 values above 32 µg/ml. Receptor binding data of Salvia extract were confirmed in native female hypothalamic tissue from two women (51 and 37 years old). Use of freshly harvested Salvia leaves resulted in 2- to 4-fold higher activity/lower IC50 values compared to extracts from dried plants or stipes. CONCLUSION: Our results suggest potent modulation of neuro-receptors and of serotonin transporters as mode of action for Salvia officinalis alcoholic extract, which may normalize thermoregulation and possibly also mental impairment during menopause.


Assuntos
Fogachos/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Salvia officinalis , Transmissão Sináptica/efeitos dos fármacos , Adulto , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Extratos Vegetais/farmacologia
15.
Nat Commun ; 10(1): 2746, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227712

RESUMO

Nicotinic acetylcholine receptors (nAChRs) mediate and modulate synaptic transmission throughout the brain, and contribute to learning, memory, and behavior. Dysregulation of α7-type nAChRs in neuropsychiatric as well as immunological and oncological diseases makes them attractive targets for pharmaceutical development. Recently, we identified NACHO as an essential chaperone for α7 nAChRs. Leveraging the robust recombinant expression of α7 nAChRs with NACHO, we utilized genome-wide cDNA library screening and discovered that several anti-apoptotic Bcl-2 family proteins further upregulate receptor assembly and cell surface expression. These effects are mediated by an intracellular motif on α7 that resembles the BH3 binding domain of pro-apoptotic Bcl-2 proteins, and can be blocked by BH3 mimetic Bcl-2 inhibitors. Overexpression of Bcl-2 member Mcl-1 in neurons enhanced surface expression of endogenous α7 nAChRs, while a combination of chemotherapeutic Bcl2-inhibitors suppressed neuronal α7 receptor assembly. These results demonstrate that Bcl-2 proteins link α7 nAChR assembly to cell survival pathways.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neurônios/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Motivos de Aminoácidos/genética , Animais , Benzotiazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Chaperonas Moleculares/metabolismo , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Piridinas/farmacologia , Pirimidinas/farmacologia , Ratos , Transmissão Sináptica/efeitos dos fármacos , Tiofenos/farmacologia , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/genética
16.
J Neuroinflammation ; 16(1): 127, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238967

RESUMO

BACKGROUND: Synaptic dysfunction, named synaptopathy, due to inflammatory status of the central nervous system (CNS) is a recognized factor potentially underlying both motor and cognitive dysfunctions in neurodegenerative diseases. To gain knowledge on the mechanistic interplay between local inflammation and synapse changes, we compared two diverse inflammatory paradigms, a cytokine cocktail (CKs; IL-1ß, TNF-α, and GM-CSF) and LPS, and their ability to tune GABAergic current duration in spinal cord cultured circuits. METHODS: We exploit spinal organotypic cultures, single-cell electrophysiology, immunocytochemistry, and confocal microscopy to explore synaptic currents and resident neuroglia reactivity upon CK or LPS incubation. RESULTS: Local inflammation in slice cultures induced by CK or LPS stimulations boosts network activity; however, only CKs specifically reduced GABAergic current duration. We pharmacologically investigated the contribution of GABAAR α-subunits and suggested that a switch of GABAAR α1-subunit might have induced faster GABAAR decay time, weakening the inhibitory transmission. CONCLUSIONS: Lower GABAergic current duration could contribute to providing an aberrant excitatory transmission critical for pre-motor circuit tasks and represent a specific feature of a CK cocktail able to mimic an inflammatory reaction that spreads in the CNS. Our results describe a selective mechanism that could be triggered during specific inflammatory stress.


Assuntos
Citocinas/toxicidade , GABAérgicos/farmacocinética , Inflamação/induzido quimicamente , Transmissão Sináptica/efeitos dos fármacos , Animais , Citocinas/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Medula Espinal , Transmissão Sináptica/imunologia
17.
Neuroscience ; 410: 183-190, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082535

RESUMO

Neuropeptide Y is a peptide neuromodulator with protective roles including anxiolytic and antidepressant-like effects in animal models of depression and post-traumatic stress disorder. The lateral habenula (LHb) is a brain region that encodes aversive information and is closely related with mood disorders. Although LHb neurons express NPY receptors, the physiological roles of NPY in this region remain uninvestigated. In this study, we examined the actions of NPY on synaptic transmission in the LHb using whole cell patch clamp recording. We observed that NPY inhibited excitatory neurotransmission in a subset of LHb neurons whereas potentiating in a small population of neurons. Inhibitory transmission remained unchanged by NPY application in a subset of neurons but was reduced in the majority of LHb neurons recorded. The overall outcome of NPY application was a decrease in the spontaneous firing rate of the LHb, leading to hypoactivation of the LHb. Our observations indicate that although NPY has divergent effects on excitatory and inhibitory transmission, NPY receptor activation decreases LHb activity, suggesting that the LHb may partly mediate the protective roles of NPY in the central nervous system.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Habenula/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Neuropeptídeo Y/farmacologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Habenula/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
18.
Mol Med Rep ; 20(1): 191-197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115527

RESUMO

Dysfunctions in dopamine (DA) and serotonin (5­HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5­HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'­iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro­positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5­HT2A receptors (5­HT2ARs) and 5­HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5­HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Neurônios Serotoninérgicos/metabolismo , Síndrome de Tourette/tratamento farmacológico , Animais , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Modelos Animais de Doenças , Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Humanos , Medicina Tradicional Chinesa , Nitrilos/toxicidade , Ratos , Receptor 5-HT2A de Serotonina/genética , Receptores de Dopamina D2/genética , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/patologia , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/genética , Síndrome de Tourette/patologia
19.
Geroscience ; 41(2): 109-123, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31041658

RESUMO

Brain-derived neurotrophic factor (BDNF) has a central role in maintaining and strengthening neuronal connections and to stimulate neurogenesis in the adult brain. Decreased levels of BDNF in the aging brain are thought to usher cognitive impairment. BDNF is stored in dense core vesicles and released through exocytosis from the neurites. The exact mechanism for the regulation of BDNF secretion is not well understood. Munc18-1 (STXBP1) was found to be essential for the exocytosis of synaptic vesicles, but its involvement in BDNF secretion is not known. Interestingly, neurons lacking munc18-1 undergo severe degeneration in knock-out mice. Here, we report the effects of BDNF treatment on the presynaptic terminal using munc18-1-deficient neurons. Reduced expression of munc18-1 in heterozygous (+/-) neurons diminishes synaptic transmitter release, as tested here on individual synaptic connections with FM1-43 fluorescence imaging. Transduction of cultured neurons with BDNF markedly increased BDNF secretion in wild-type but was less effective in munc18-1 +/- cells. In turn, BDNF enhanced synaptic functions and restored the severe synaptic dysfunction induced by munc18-1 deficiency. The role of munc18-1 in the synaptic effect of BDNF is highlighted by the finding that BDNF upregulated the expression of munc18-1 in neurons, consistent with enhanced synaptic functions. Accordingly, this is the first evidence showing the functional effect of BDNF in munc18-1 deficient synapses and about the direct role of munc18-1 in the regulation of BDNF secretion. We propose a molecular model of BDNF secretion and discuss its potential as therapeutic target to prevent cognitive decline in the elderly.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Disfunção Cognitiva/metabolismo , Proteínas Munc18/metabolismo , Proteínas SNARE/metabolismo , Envelhecimento/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/fisiopatologia , Humanos , Camundongos , Camundongos Knockout , Ligação Proteica , Sensibilidade e Especificidade , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas
20.
Eur J Pharmacol ; 855: 305-320, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31067439

RESUMO

This review examines the functions of α1-adrenoceptor subtypes, particularly in terms of contraction of smooth muscle. There are 3 subtypes of α1-adrenoceptor, α1A- α1B- and α1D-adrenoceptors. Evidence is presented that the postulated α1L-adrenoceptor is simply the native α1A-adrenoceptor at which prazosin has low potency. In most isolated tissue studies, smooth muscle contractions to exogenous agonists are mediated particularly by α1A-, with a lesser role for α1D-adrenoceptors, but α1B-adrenoceptors are clearly involved in contractions of some tissues, for example, the spleen. However, nerve-evoked responses are the most crucial physiologically, so that these studies of exogenous agonists may overestimate the importance of α1A-adrenoceptors. The major α1-adrenoceptors involved in blood pressure control by sympathetic nerves are the α1D- and the α1A-adrenoceptors, mediating peripheral vasoconstrictor actions. As noradrenaline has high potency at α1D-adrenceptors, these receptors mediate the fastest response and seem to be targets for neurally released noradrenaline especially to low frequency stimulation, with α1A-adrenoceptors being more important at high frequencies of stimulation. This is true in rodent vas deferens and may be true in vasopressor nerves controlling peripheral resistance and tissue blood flow. The αlA-adrenoceptor may act mainly through Ca2+ entry through L-type channels, whereas the α1D-adrenoceptor may act mainly through T-type channels and exhaustable Ca2+ stores. α1-Adrenoceptors may also act through non-G-protein linked second messenger systems. In many tissues, multiple subtypes of α-adrenoceptor are present, and this may be regarded as the norm rather than exception, although one receptor subtype is usually predominant.


Assuntos
Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Humanos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Prazosina/metabolismo , Prazosina/farmacologia , Transmissão Sináptica/efeitos dos fármacos
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