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1.
Glia ; 70(12): 2330-2347, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35916350

RESUMO

Parkinson's disease (PD) is associated with an increase in secreted S100B within the midbrain and cerebrospinal fluid. In addition, S100B overexpression in mice accelerates the loss of substantia nigra pars compacta dopaminergic (DA) neurons, suggesting a role for this protein in PD pathogenesis. We found that in the mouse SNc, S100B labeled astrocytic processes completely envelop the somata of tyrosine hydroxylase (TH) expressing DA neurons only in male mice. These data suggest that an increase in S100B secretion by astrocytes within the midbrain could play a role in DA dysfunction during early PD. We therefore asked if acute exposure to extracellular S100B alters the activity of identified TH expressing DA neurons in primary mouse midbrain cultures. Acute exposure to 50 pM S100B specifically inhibited A-type voltage-gated potassium currents in TH+ , but not TH- neurons. This was accompanied by ~2-fold increases in the frequency of both intrinsic firing, as well as L-type voltage-gated calcium channel (VGCC)-mediated calcium fluxes only in TH+ neurons. Further, exposure to 100 µM 4-aminopyridine (4-AP), an A-type voltage-gated potassium channel inhibitor, mimicked the S100B mediated increase in intrinsic firing and L-type VGCC-mediated calcium fluxes in TH+ neurons. Taken together, our finding that extracellular S100B alters the activity of native DA neurons via an inhibition of A-type voltage-gated potassium channels has important implications for understanding the pathophysiology of early PD.


Assuntos
Doença de Parkinson , Canais de Potássio de Abertura Dependente da Tensão da Membrana , 4-Aminopiridina , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Neurônios Dopaminérgicos/metabolismo , Masculino , Camundongos , Doença de Parkinson/metabolismo , Potássio/metabolismo , Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
2.
J Neurochem ; 157(3): 710-726, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33354763

RESUMO

Apoptotic endoplasmic reticulum (ER) stress is a major mechanism for dopaminergic (DA) loss in Parkinson's disease (PD). We assessed if low doses of the partial α4ß2 nicotinic acetylcholine receptor agonist, cytisine attenuates apoptotic ER stress and exerts neuroprotection in substantia nigra pars compacta (SNc) DA neurons. Alternate day intraperitoneal injections of 0.2 mg/kg cytisine were administered to female and male mice with 6-hydroxydopamine (6-OHDA) lesions in the dorsolateral striatum, which caused unilateral degeneration of SNc DA neurons. Cytisine attenuated 6-OHDA-induced PD-related behaviors in female, but not in male mice. We also found significant reductions in tyrosine hydroxylase (TH) loss within the lesioned SNc of female, but not male mice. In contrast to female mice, DA neurons within the lesioned SNc of male mice showed a cytisine-induced pathological increase in the nuclear translocation of the pro-apoptotic ER stress protein, C/EBP homologous protein (CHOP). To assess the role of estrogen in cytisine neuroprotection in female mice, we exposed primary mouse DA cultures to either 10 nM 17-ß-estradiol and 200 nM cytisine or 10 nM 17-ß-estradiol alone. 17-ß-estradiol reduced expression of CHOP, whereas cytisine exposure reduced 6-OHDA-mediated nuclear translocation of two other ER stress proteins, activating transcription factor 6 and x-box-binding protein 1, but not CHOP. Taken together, these data show that cytisine and 17-ß-estradiol work in combination to inhibit all three arms (activating transcription factor 6, x-box-binding protein 1, and CHOP) of apoptotic ER stress signaling in DA neurons, which can explain the neuroprotective effect of low-dose cytisine in female mice.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estradiol/farmacologia , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Fator 6 Ativador da Transcrição/efeitos dos fármacos , Animais , Azocinas/farmacologia , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/psicologia , Cultura Primária de Células , Quinolizinas/farmacologia , Caracteres Sexuais , Substância Negra/efeitos dos fármacos , Simpatolíticos , Fator de Transcrição CHOP/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Front Physiol ; 12: 812212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35087422

RESUMO

Astrocytes display a plethora of spontaneous Ca2+ signals that modulate vital functions of the central nervous system (CNS). This suggests that astrocytic Ca2+ signals also contribute to pathological processes in the CNS. In this context, the molecular mechanisms by which aberrant astrocytic Ca2+ signals trigger dopaminergic neuron loss during Parkinson's disease (PD) are only beginning to emerge. Here, we provide an evidence-based perspective on potential mechanisms by which aberrant astrocytic Ca2+ signals can trigger dysfunction in three distinct compartments of the brain, viz., neurons, microglia, and the blood brain barrier, thereby leading to PD. We envision that the coming decades will unravel novel mechanisms by which aberrant astrocytic Ca2+ signals contribute to PD and other neurodegenerative processes in the CNS.

4.
J Vis Exp ; (163)2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986023

RESUMO

Parkinson's disease (PD) is a devastating neurodegenerative disorder caused by the degeneration of dopaminergic (DA) neurons. Excessive Ca2+ influx due to the abnormal activation of glutamate receptors results in DA excitotoxicity and has been identified as an important mechanism for DA neuron loss. In this study, we isolate, dissociate, and culture midbrain neurons from the mouse ventral mesencephalon (VM) of ED14 mouse embryos. We then infect the long-term primary mouse midbrain cultures with an adeno-associated virus (AAV) expressing a genetically encoded calcium indicator, GCaMP6f under control of the human neuron-specific synapsin promoter, hSyn. Using live confocal imaging, we show that cultured mouse midbrain neurons display spontaneous Ca2+ fluxes detected by AAV-hSyn-GCaMP6f. Bath application of glutamate to midbrain cultures causes abnormal elevations in intracellular Ca2+ within neurons and this is accompanied by caspase-3 activation in DA neurons, as demonstrated by immunostaining. The techniques to identify glutamate-mediated apoptosis in primary mouse DA neurons have important applications for the high content screening of drugs that preserve DA neuron health.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Neurônios Dopaminérgicos/citologia , Mesencéfalo/citologia , Animais , Caspase 3/metabolismo , Células Cultivadas , Dependovirus/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Embrião de Mamíferos/citologia , Vetores Genéticos/metabolismo , Glutamatos/farmacologia , Processamento de Imagem Assistida por Computador , Camundongos , Quinoxalinas/farmacologia , Receptores de AMPA/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Alcohol ; 71: 75-87, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30059955

RESUMO

Perinatal ethanol exposure disrupts a variety of developmental processes in neurons important for establishing a healthy brain. These ethanol-induced impairments known as fetal alcohol spectrum disorder (FASD) are not fully understood, and currently, there is no effective treatment. Further, growing evidence suggests that adult females are more susceptible to ethanol, with the effects of perinatal ethanol exposure also being sexually divergent. Female models have been historically underutilized in neurophysiological investigations, but here, we used a third-trimester binge-ethanol model of FASD to examine changes to basal forebrain (BF) physiology and behavior in female Sprague-Dawley rats. We also tested varenicline as a potential cholinomimetic therapeutic. Rat pups were gavage-treated with binge-like ethanol, varenicline and ethanol, and varenicline alone. Using patch-clamp electrophysiology in BF slices, we observed that binge-ethanol exposure increased spontaneous post-synaptic current (sPSC) frequency. Varenicline exposure alone also enhanced sPSC frequency. Varenicline plus ethanol co-treatment prevented the sPSC frequency increase. Changes in BF synaptic transmission persisted into adolescence after binge-ethanol treatment. Behaviorally, binge-ethanol treated females displayed increased anxiety (thigmotaxis) and demonstrated learning deficits in the water maze. Varenicline/ethanol co-treatment was effective at reducing these behavioral deficits. In the open field, ethanol-treated rats displayed longer distances traveled and spent less time in the center of the open field box. Co-treated rats displayed less anxiety, demonstrating a possible effect of varenicline on this measure. In conclusion, ethanol-induced changes in both BF synaptic transmission and behavior were reduced by varenicline in female rats, supporting a role for cholinergic therapeutics in FASD treatment.


Assuntos
Etanol/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/terapia , Vareniclina/farmacologia , Animais , Ansiedade/prevenção & controle , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/fisiopatologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Gravidez , Terceiro Trimestre da Gravidez , Ratos
6.
J Neurotrauma ; 34(6): 1164-1174, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-27736318

RESUMO

Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the κ-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using nor-Binaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 µmol) followed by morphine (0 or 0.32 µmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphine-induced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Morfina/administração & dosagem , Morfina/efeitos adversos , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Entorpecentes/administração & dosagem , Entorpecentes/efeitos adversos , Ratos , Ratos Sprague-Dawley
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