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1.
Pflugers Arch ; 475(2): 233-248, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36289078

RESUMO

One side effect of cisplatin, a cytotoxic platinum anticancer drug, is peripheral neuropathy; however, its central nervous system effects remain unclear. We monitored respiratory nerve activity from the C4 ventral root in brainstem and spinal cord preparations from neonatal rats (P0-3) to investigate its central effects. Bath application of 10-100 µM cisplatin for 15-20 min dose-dependently decreased the respiratory rate and increased the amplitude of C4 inspiratory activity. These effects were not reversed after washout. In separate perfusion experiments, cisplatin application to the medulla decreased the respiratory rate, and application to the spinal cord increased the C4 burst amplitude without changing the burst rate. Application of other platinum drugs, carboplatin or oxaliplatin, induced no change of respiratory activity. A membrane potential analysis of respiratory-related neurons in the rostral medulla showed that firing frequencies of action potentials in the burst phase tended to decrease during cisplatin application. In contrast, in inspiratory spinal motor neurons, cisplatin application increased the peak firing frequency of action potentials during the inspiratory burst phase. The increased burst amplitude and decreased respiratory frequency were partially antagonized by riluzole and picrotoxin, respectively. Taken together, cisplatin inhibited respiratory rhythm via medullary inhibitory system activation and enhanced inspiratory motor nerve activity by changing the firing property of motor neurons.


Assuntos
Cisplatino , Taxa Respiratória , Ratos , Animais , Animais Recém-Nascidos , Cisplatino/farmacologia , Ratos Wistar , Platina , Bulbo/fisiologia , Medula Espinal , Neurônios Motores , Respiração
2.
Pflugers Arch ; 475(11): 1301-1314, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37707585

RESUMO

Aconitine is a sodium channel opener, but its effects on the respiratory center are not well understood. We investigated the dose-dependent effects of aconitine on central respiratory activity in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 0.5-5 µM aconitine caused an increase in respiratory rhythm and decrease in the inspiratory burst amplitude of the fourth cervical ventral root (C4). Separate application of aconitine revealed that medullary neurons were responsible for the respiratory rhythm increase, and neurons in both the medulla and spinal cord were involved in the decrease of C4 amplitude by aconitine. A local anesthetic, lidocaine (100 µM), or a voltage-dependent sodium channel blocker, tetrodotoxin (0.1 µM), partially antagonized the C4 amplitude decrease by aconitine. Tetrodotoxin treatment tentatively decreased the respiratory rhythm, but lidocaine tended to further increase the rhythm. Treatment with 100 µM riluzole or 100 µM flufenamic acid, which are known to inhibit respiratory pacemaker activity, did not reduce the respiratory rhythm enhanced by aconitine + lidocaine. The application of 1 µM aconitine depolarized the preinspiratory, expiratory, and inspiratory motor neurons. The facilitated burst rhythm of inspiratory neurons after aconitine disappeared in a low Ca2+/high Mg2+ synaptic blockade solution. We showed the dose-dependent effects of aconitine on respiratory activity. The antagonists reversed the depressive effects of aconitine in different manners, possibly due to their actions on different sites of sodium channels. The burst-generating pacemaker properties of neurons may not be involved in the generation of the facilitated rhythm after aconitine treatment.


Assuntos
Aconitina , Tronco Encefálico , Animais , Ratos , Animais Recém-Nascidos , Aconitina/farmacologia , Tetrodotoxina/farmacologia , Ratos Wistar , Bulbo/fisiologia , Medula Espinal , Lidocaína/farmacologia
3.
Can J Physiol Pharmacol ; 101(2): 65-73, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36524681

RESUMO

Antenatal steroid administration to pregnant women at risk of prematurity provides pulmonary maturation in infants, while it has limited effects on incidence of bronchopulmonary dysplasia (BPD), the clinical expression of hyperoxia-induced lung injury (HILI). Cytidine-5'-diphosphate choline (CDP-choline) was shown to alleviate HILI when administered to newborn rats. Therefore, we investigated effects of maternal administration of CDP-choline, alone or in combination with betamethasone, on lung maturation in neonatal rats subjected to HILI immediately after birth. Pregnant rats were randomly assigned to one of the four treatments: saline (1 mL/kg), CDP-choline (300 mg/kg), betamethasone (0.4 mg/kg), or CDP-choline plus betamethasone (combination therapy). From postnatal day 1 to 11, pups born to mothers in the same treatment group were pooled and randomly assigned to either normoxia or hyperoxia group. Biochemical an d histopathological effects of CDP-choline on neonatal lung tissue were evaluated. Antenatal CDP-choline treatment increased levels of phosphatidylcholine and total lung phospholipids, decreased apoptosis, and improved alveolarization. The outcomes were further improved with combination therapy compared to the administration of CDP-choline or betamethasone alone. These results demonstrate that antenatal CDP-choline treatment provides benefit in experimental HILI either alone or more intensively when administered along with a steroid, suggesting a possible utility for CDP-choline against BPD.


Assuntos
Displasia Broncopulmonar , Hiperóxia , Lesão Pulmonar , Animais , Ratos , Feminino , Gravidez , Humanos , Recém-Nascido , Citidina Difosfato Colina/farmacologia , Citidina Difosfato Colina/uso terapêutico , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/metabolismo , Hiperóxia/complicações , Hiperóxia/metabolismo , Hiperóxia/patologia , Animais Recém-Nascidos , Pulmão/metabolismo , Betametasona/farmacologia , Betametasona/uso terapêutico , Betametasona/metabolismo , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/prevenção & controle
4.
Int J Mol Sci ; 24(9)2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-37175511

RESUMO

The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum.


Assuntos
Dexmedetomidina , Hiperóxia , Recém-Nascido , Animais , Ratos , Humanos , Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Ratos Wistar , Animais Recém-Nascidos , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Recém-Nascido Prematuro , Apoptose , Estresse Oxidativo , Oxigênio/farmacologia , Interneurônios
5.
Int J Mol Sci ; 24(19)2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37834195

RESUMO

L-DOPA, the precursor of catecholamines, exerts a pro-locomotor action in several vertebrate species, including newborn rats. Here, we tested the hypothesis that decreasing the degradation of monoamines can promote the pro-locomotor action of a low, subthreshold dose of L-DOPA in five-day-old rats. The activity of the degrading pathways involving monoamine oxidases or catechol-O-methyltransferase was impaired by injecting nialamide or tolcapone, respectively. At this early post-natal stage, the capacity of the drugs to trigger locomotion was investigated by monitoring the air-stepping activity expressed by the animals suspended in a harness above the ground. We show that nialamide (100 mg/kg) or tolcapone (100 mg/kg), without effect on their own promotes maximal expression of air-stepping sequences in the presence of a sub-effective dose of L-DOPA (25 mg/kg). Tissue measurements of monoamines (dopamine, noradrenaline, serotonin and some of their metabolites) in the cervical and lumbar spinal cord confirmed the regional efficacy of each inhibitor toward their respective enzyme. Our experiments support the idea that the raise of monoamines boost L-DOPA's locomotor action. Considering that both inhibitors differently altered the spinal monoamines levels in response to L-DOPA, our data also suggest that maximal locomotor response can be reached with different monoamines environment.


Assuntos
Catecol O-Metiltransferase , Levodopa , Ratos , Animais , Levodopa/farmacologia , Levodopa/metabolismo , Tolcapona/farmacologia , Animais Recém-Nascidos , Nialamida , Locomoção
6.
Can J Physiol Pharmacol ; 100(12): 1106-1114, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36223651

RESUMO

In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart's development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly cultured ventricular cardiomyocytes from newborn and adult rats. Our results showed that the cytosolic basal level of calcium was higher in newborn cardiomyocytes with no change in the nuclear basal calcium level compared with the adult cardiomyocytes; in addition, insulin induced a slow increase of cytosolic and nuclear calcium in newborn ventricular cardiomyocytes, followed by two phases. However, the first phase of slow cytosolic and nuclear calcium increase was absent in adult rat ventricular cardiomyocytes. Furthermore, the time to the onset of increase of cytosolic and nuclear calcium was longer in newborn cardiomyocytes compared with adults. Moreover, the time to peak of the calcium transient was shorter in newborns than in adult cardiomyocytes. These results demonstrate that insulin differently regulates calcium homeostasis in newborns than in adult cardiomyocytes. Thus, newborn rat cardiomyocytes, commonly used in research as a model for adult cardiomyocytes, should be used with caution when dealing with insulin in normal and disease conditions.


Assuntos
Cálcio , Miócitos Cardíacos , Ratos , Animais , Cálcio/farmacologia , Insulina/farmacologia , Células Cultivadas , Ventrículos do Coração
7.
Int J Neurosci ; 129(11): 1139-1144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31234674

RESUMO

Aim: The aim of the present study is to investigate the neuroprotective effects of l-Arginine (l-arg) in the seven-day-old rat hypoxia-ischemia model. Materials and methods: L-Arginine (n = 10) or saline (n = 8) was administered intraperitoneally to seven-day-old rats before hypoxia-ischemia. In addition, 18 seven-day-old rats were given l-Arginine (n = 10) or saline (n = 8) after hypoxic-ischemic insult. Neuronal apoptosis was investigated by terminal dUDP-biotin nick end-labeling (TUNEL) following three days of recovery. The ratios of right side numerical density to the sum of right and left sides' numerical densities (right apoptosis index) were calculated for every brain region in rats receiving l-arginine and they were compared with the vehicle groups. Results: Right side apoptosis indexes of the hippocampus (mean ± SD; 35.0 ± 16.1) and striatum (41.9 ± 16.0) were significantly decreased in the l-Arginine post-treatment groups when compared to vehicles (61.0 ± 17.0 and 62.4 ± 27.0 respectively) (p < 0.05). There was no significant difference in the right apoptosis indexes of the cortex between l-Arginine post-treated group and the vehicle group. There were also no significant differences between the right side apoptosis indexes of the l-Arginine pretreatment groups and those of the vehicle group in any of the three regions (p > 0.05). Conclusions: It is concluded that neuronal apoptosis due to hypoxic-ischemic injury may likely to be reduced by post-treatment of l-Arginine in the neonatal rat model and l-Arginine provides a new possibility for neuroprotective strategies based on NO production.


Assuntos
Apoptose/efeitos dos fármacos , Arginina/farmacologia , Corpo Estriado , Hipocampo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Arginina/administração & dosagem , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar
8.
Exp Brain Res ; 236(6): 1767-1774, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29654351

RESUMO

Eugenol is contained in several plants including clove and is thought to exert an analgesic effect. It has been suggested that the slow ventral root potential induced by ipsilateral dorsal root stimulation in the isolated (typically lumbar) spinal cord of newborn rats reflects the nociceptive response, and this in vitro experimental model is useful to assess the actions of analgesics. To further elucidate neuronal mechanisms of eugenol-induced analgesia, we examined the effects of extracellularly applied eugenol on the nociceptive spinal reflex response. To evaluate the effects of eugenol on putative nociceptive responses, the ipsilateral fifth lumbar (L5) dorsal root was stimulated using a glass suction electrode, and the induced reflex responses were recorded from the L5 and twelfth thoracic (Th12) ventral roots in spinal cord preparations (Th10-L5) from newborn rats (postnatal day 0-3). We found that eugenol (0.25-1.0 mM) caused dose-dependent attenuation of the reflex response and also depressed spontaneous ventral root activity. We also found that the slow ventral root potential was further divided into two components: initial and late components. A lower concentration of eugenol selectively depressed the late component. The inhibitory effects by 1.0 mM eugenol were not reversed by 10 µM capsazepine (TRPV1 antagonist) or 40 µM HC-030031 (TRPA1 antagonist). The depressive effect of eugenol on the reflex response was also confirmed by optical recordings using voltage-sensitive dye. Our report provides additional evidence on the basic neuronal mechanisms of eugenol to support its clinical use as a potential analgesic treatment.


Assuntos
Analgésicos/farmacologia , Eugenol/farmacologia , Potenciais Evocados/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Raízes Nervosas Espinhais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Estimulação Elétrica , Imagem Óptica , Ratos , Ratos Wistar
9.
J Neurosci ; 36(3): 926-37, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26791221

RESUMO

Neural networks that can generate rhythmic motor output in the absence of sensory feedback, commonly called central pattern generators (CPGs), are involved in many vital functions such as locomotion or respiration. In certain circumstances, these neural networks must interact to produce coordinated motor behavior adapted to environmental constraints and to satisfy the basic needs of an organism. In this context, we recently reported the existence of an ascending excitatory influence from lumbar locomotor CPG circuitry to the medullary respiratory networks that is able to depolarize neurons of the parafacial respiratory group during fictive locomotion and to subsequently induce an increased respiratory rhythmicity (Le Gal et al., 2014b). Here, using an isolated in vitro brainstem-spinal cord preparation from neonatal rat in which the respiratory and the locomotor networks remain intact, we show that during fictive locomotion induced either pharmacologically or by sacrocaudal afferent stimulation, the activity of both thoracolumbar expiratory motoneurons and interneurons is rhythmically modulated with the locomotor activity. Completely absent in spinal inspiratory cells, this rhythmic pattern is highly correlated with the hindlimb ipsilateral flexor activities. Furthermore, silencing brainstem neural circuits by pharmacological manipulation revealed that this locomotor-related drive to expiratory motoneurons is solely dependent on propriospinal pathways. Together these data provide the first evidence in the newborn rat spinal cord for the existence of bimodal respiratory-locomotor motoneurons and interneurons onto which both central efferent expiratory and locomotor drives converge, presumably facilitating the coordination between the rhythmogenic networks responsible for two different motor functions. Significance statement: In freely moving animals, distant regions of the brain and spinal cord controlling distinct motor acts must interact to produce the best adapted behavioral response to environmental constraints. In this context, it is well established that locomotion and respiration must to be tightly coordinated to reduce muscular interferences and facilitate breathing rate acceleration during exercise. Here, using electrophysiological recordings in an isolated in vitro brainstem-spinal cord preparation from neonatal rat, we report that the locomotor-related signal produced by the lumbar central pattern generator for locomotion selectively modulates the intracellular activity of spinal respiratory neurons engaged in expiration. Our results thus contribute to our understanding of the cellular bases for coordinating the rhythmic neural circuitry responsible for different behaviors.


Assuntos
Potenciais de Ação/fisiologia , Atividade Motora/fisiologia , Neurônios Motores/fisiologia , Mecânica Respiratória/fisiologia , Medula Espinal/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Ratos , Ratos Sprague-Dawley
10.
Cereb Cortex ; 23(6): 1299-316, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22593243

RESUMO

Neocortical areas are organized in columns, which form the basic structural and functional modules of intracortical information processing. Using voltage-sensitive dye imaging and simultaneous multi-channel extracellular recordings in the barrel cortex of newborn rats in vivo, we found that spontaneously occurring and whisker stimulation-induced gamma bursts followed by longer lasting spindle bursts were topographically organized in functional cortical columns already at the day of birth. Gamma bursts synchronized a cortical network of 300-400 µm in diameter and were coherent with gamma activity recorded simultaneously in the thalamic ventral posterior medial (VPM) nucleus. Cortical gamma bursts could be elicited by focal electrical stimulation of the VPM. Whisker stimulation-induced spindle and gamma bursts and the majority of spontaneously occurring events were profoundly reduced by the local inactivation of the VPM, indicating that the thalamus is important to generate these activity patterns. Furthermore, inactivation of the barrel cortex with lidocaine reduced the gamma activity in the thalamus, suggesting that a cortico-thalamic feedback loop modulates this early thalamic network activity.


Assuntos
Relógios Biológicos/fisiologia , Mapeamento Encefálico , Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Núcleos Ventrais do Tálamo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Anestésicos Locais/farmacologia , Animais , Animais Recém-Nascidos , Estimulação Elétrica , Eletrólitos/efeitos adversos , Retroalimentação Fisiológica , Lidocaína/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Córtex Somatossensorial/crescimento & desenvolvimento , Estatísticas não Paramétricas , Vibrissas/inervação , Imagens com Corantes Sensíveis à Voltagem
11.
Respir Physiol Neurobiol ; 321: 104207, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38160896

RESUMO

We examined respiratory sinus arrhythmia (RSA) and possible interaction with respiratory frequency (fR) and heart rate (HR) in spontaneously breathing, unanesthetized newborn Wistar rats (2- to 5-day-old; n = 54) and the adult rats (8-week-old; n = 34). Instantaneous heart rate (inst-HR) was calculated as the reciprocal of the inter-beat-interval. For each breath, RSA was determined as the difference between the maximum and minimum inst-HR value. The absolute RSA or RSA% (RSA per HR) were calculated as the average RSA of 10 consecutive breaths. RSA (or RSA%) in the newborn rats was significantly lower than that in the adult rats. Correlation coefficient between RSA (or RSA%) and 1/fR or HR/fR, but not HR, was significant in newborn rats, whereas only that between RSA (or RSA%) and HR was significant in adult rats. The power spectrum density of heartbeat fluctuation was detectable in both age groups. The present findings suggest that RSA exists and could be influenced by fR, rather than HR, in newborn rats.


Assuntos
Arritmia Sinusal Respiratória , Ratos , Animais , Arritmia Sinusal Respiratória/fisiologia , Ratos Wistar , Arritmia Sinusal , Respiração , Frequência Cardíaca/fisiologia
12.
Antioxidants (Basel) ; 12(2)2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36829854

RESUMO

High-risk preterm infants are affected by a higher incidence of cognitive developmental deficits due to the unavoidable risk factor of oxygen toxicity. Caffeine is known to have a protective effect in preventing bronchopulmonary dysplasia associated with improved neurologic outcomes, although very early initiation of therapy is controversial. In this study, we used newborn rats in an oxygen injury model to test the hypothesis that near-birth caffeine administration modulates neuronal maturation and differentiation in the hippocampus of the developing brain. For this purpose, newborn Wistar rats were exposed to 21% or 80% oxygen on the day of birth for 3 or 5 days and treated with vehicle or caffeine (10 mg/kg/48 h). Postnatal exposure to 80% oxygen resulted in a drastic reduction of associated neuronal mediators for radial glia, mitotic/postmitotic neurons, and impaired cell-cycle regulation, predominantly persistent even after recovery to room air until postnatal day 15. Systemic caffeine administration significantly counteracted the effects of oxygen insult on neuronal maturation in the hippocampus. Interestingly, under normoxia, caffeine inhibited the transcription of neuronal mediators of maturing and mature neurons. The early administration of caffeine modulated hyperoxia-induced decreased neurogenesis in the hippocampus and showed neuroprotective properties in the neonatal rat oxygen toxicity model.

13.
J Physiol Sci ; 73(1): 23, 2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37803279

RESUMO

A metabolite of acetaminophen, AM404, which is an anandamide transporter inhibitor, induces analgesia mainly via activation of transient receptor potential channel 1 in the spinal cord, although the role of cannabinoid receptors remains to be studied. The ventral root reflex response induced by stimulation of the dorsal root in in vitro preparations of rat spinal cord is useful to assess the effect of analgesics. We analyzed the effects of AM404 and cannabinoid receptor antagonist AM251 on reflex responses in lumbar spinal cord preparations from newborn rats and found that the amplitude of the slow ventral root potential after administration of 10 µM AM404 was not significantly changed, whereas 10 µM AM251 significantly increased the amplitude. Administration of the cannabinoid receptor 1 agonist WIN55,212-2 (10 µM) did not significantly affect the reflex response. We suggest that endogenous cannabinoids in the spinal cord are involved in the antinociceptive mechanism through suppressive effects.


Assuntos
Nociceptividade , Medula Espinal , Ratos , Animais , Animais Recém-Nascidos , Ratos Wistar , Receptores de Canabinoides/metabolismo
14.
Neuroscience ; 528: 89-101, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37557948

RESUMO

Proteinase-activated receptor-1 (PAR1) is expressed in astrocytes of various brain regions, and its activation is involved in the modulation of neuronal activity. Here, we report effects of PAR1 selective agonist TFLLR on respiratory rhythm generation in brainstem-spinal cord preparations. Preparations were isolated from newborn rats (P0-P4) under deep isoflurane anesthesia and were transversely cut at the rostral medulla. Preparations were superfused with artificial cerebrospinal fluid (25-26 °C), and inspiratory C4 ventral root activity was monitored. The responses to TFLLR of cells close to the cut surface were detected by calcium imaging or membrane potential recordings. Application of 10 µM TFLLR (4 min) induced a rapid and transient increase of calcium signal in cells of the ventrolateral respiratory regions of the medulla. More than 88% of responding cells (223/254 cells from 13 preparations) were also activated by low (0.2 mM) K+ solution, suggesting that they were astrocytes. Immunohistochemical examination demonstrated that PAR1 was expressed on many astrocytes. Respiratory-related neurons in the medulla were transiently hyperpolarized (-1.8 mV) during 10 µM TFLLR application, followed by weak membrane depolarization after washout. C4 burst rate decreased transiently in response to application of TFLLR, followed by a slight increase. The inhibitory effect was partially blocked by 50 µM theophylline. In conclusion, activation of astrocytes via PAR1 resulted in a decrease of inspiratory C4 burst rate in association with transient hyperpolarization of respiratory-related neurons. After washout, slow and weak excitatory responses appeared. Adenosine may be partially involved in the inhibitory effect of PAR1 activation.


Assuntos
Cálcio , Receptor PAR-1 , Animais , Ratos , Animais Recém-Nascidos , Ratos Wistar , Tronco Encefálico/fisiologia , Bulbo , Medula Espinal
15.
Antioxidants (Basel) ; 12(4)2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37107355

RESUMO

Impaired cerebellar development of premature infants and the associated impairment of cerebellar functions in cognitive development could be crucial factors for neurodevelopmental disorders. Anesthetic- and hyperoxia-induced neurotoxicity of the immature brain can lead to learning and behavioral disorders. Dexmedetomidine (DEX), which is associated with neuroprotective properties, is increasingly being studied for off-label use in the NICU. For this purpose, six-day-old Wistar rats (P6) were exposed to hyperoxia (80% O2) or normoxia (21% O2) for 24 h after DEX (5 µg/kg, i.p.) or vehicle (0.9% NaCl) application. An initial detection in the immature rat cerebellum was performed after the termination of hyperoxia at P7 and then after recovery in room air at P9, P11, and P14. Hyperoxia reduced the proportion of Calb1+-Purkinje cells and affected the dendrite length at P7 and/or P9/P11. Proliferating Pax6+-granule progenitors remained reduced after hyperoxia and until P14. The expression of neurotrophins and neuronal transcription factors/markers of proliferation, migration, and survival were also reduced by oxidative stress in different manners. DEX demonstrated protective effects on hyperoxia-injured Purkinje cells, and DEX without hyperoxia modulated neuronal transcription in the short term without any effects at the cellular level. DEX protects hyperoxia-damaged Purkinje cells and appears to differentially affect cerebellar granular cell neurogenesis following oxidative stress.

16.
Clin Exp Pharmacol Physiol ; 38(3): 186-91, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21251047

RESUMO

1. Propofol (2,6-diisopropylphenol) is an intravenous anaesthetic used for the induction and maintenance of general anaesthesia; it also potently and dose-dependently depresses respiration. The aim of the present study was to analyse propofol-induced changes in spatiotemporal patterns of inspiratory-related neural activity and to investigate the involvement of the GABAA receptor by using an optical imaging technique. 2. The brain stems and spinal cords of 0-1-day-old Wistar rats were isolated and stained using a fluorescent voltage-sensitive dye. Neuronal activity in the preparation was detected using an optical recording apparatus containing a charge-coupled device (CCD)-based camera. 3. Bath-applied propofol (7.5 µmol/L) decreased the C4 burst rate to 45.9% of baseline. Although optical signals corresponding to membrane depolarization during the pre-inspiratory phase in the parafacial region of the ventral medulla decreased to 28.7% of baseline following propofol application, those during the inspiratory phase in the caudal part of the rostral ventrolateral medulla did not. 4. The inhibitory effect of bath-applied propofol was reversed by 2 µmol/L bicuculline. 5. Changes in optical signals corresponding to the population activity of pre-inspiratory neurons were parallel to changes in the C4 burst rate. 6. The results suggest that propofol decreases the inspiratory burst rate by reducing the activity of pre-inspiratory neurons and that GABAA receptor activation plays a role in propofol-induced central respiratory depression. These results are consistent with those of previous electrophysiological studies.


Assuntos
Bulbo/efeitos dos fármacos , Propofol/farmacologia , Respiração/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Animais , Animais Recém-Nascidos , Bulbo/metabolismo , Bulbo/patologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Imagem Óptica , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/patologia , Medula Espinal/metabolismo
17.
Respir Physiol Neurobiol ; 293: 103737, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34229065

RESUMO

Effects of acetylcholine (ACh) on respiratory activity have been an intriguing theme especially in relation to central chemoreception and the control of hypoglossal nerve activity. We studied the effects of ACh on hypoglossal and phrenic (C4) nerve activities and inspiratory and pre-inspiratory neurons in the rostral ventrolateral medulla in brainstem-spinal cord preparations from newborn rats. ACh application increased respiratory rhythm, decreased inspiratory hypoglossal and C4 nerve burst amplitude, and enhanced pre-inspiratory hypoglossal activity. ACh induced membrane depolarization of pre-inspiratory neurons that might be involved in facilitation of respiratory rhythm by ACh. Effects of ACh on hypoglossal and C4 nerve activity were partially reversed by a nicotinic receptor blocker, mecamylamine. Further application of a muscarinic receptor antagonist, oxybutynin, resulted in slight increase of hypoglossal (but not C4) burst amplitude. Thus, ACh induced different effects on hypoglossal and C4 nerve activity in the brainstem-spinal cord preparation.


Assuntos
Acetilcolina/farmacologia , Tronco Encefálico/efeitos dos fármacos , Nervo Hipoglosso/efeitos dos fármacos , Nervo Frênico/efeitos dos fármacos , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Células Quimiorreceptoras/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Front Physiol ; 11: 614283, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33519519

RESUMO

Perinatal inflammation due to chorioamnionitis and ventilator-induced lung injury (VILI) at birth is independent risk factors for the development of bronchopulmonary dysplasia (BPD). We have previously shown that antenatal endotoxin (ETX) causes abnormal lung structure and function in 2-week-old rats, but whether ETX impairs lung mechanics at birth and increases risk for VILI is unknown. Fetal rats were exposed to 10 µg endotoxin or saline via intra-amniotic injection. At birth (D0) or 7 days (D7), rats received 90 min of lung protective ventilation [PROTECT group; tidal volume (Vt) = 6 ml/kg with positive end expiratory pressure (PEEP) = 2 cmH2O]; P20 ventilation [plateau pressure (Pplat) = 20 cmH2O, PEEP = 0]; or P24 ventilation (Pplat = 24 cmH2O, PEEP = 0, only applied to D7). Prior to prolonged ventilation at D0, endotoxin-exposed rats had decreased compliance and inspiratory capacity (IC) compared to controls. At D7, endotoxin was associated with reduced compliance. High-pressure ventilation (P20 and P24) tended to increase IC and compliance in all saline-treated groups. Ventilation at D0 with P20 increased IC and compliance when applied to saline-treated but not endotoxin-exposed pups. At D7, P24 ventilation of endotoxin-exposed pups increased elastance, bronchoalveolar lavage protein content, and IL-1b and TEN-C mRNA expression in comparison to the saline group. In summary, antenatal endotoxin exposure alters lung mechanics at birth and 1 week of life and increases susceptibility to VILI as observed in lung mechanics, alveolocapillary barrier injury, and inflammatory mRNA expression. We speculate that antenatal inflammation primes the lung for a more marked VILI response, suggesting an adverse synergistic effect of antenatal and postnatal exposures.

19.
J Clin Neurosci ; 78: 365-370, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32360159

RESUMO

To explore the effects of p38 MAPK signaling pathway on cognitive function and recovery of neuronal function after hypoxic-ischemic brain injury (HIBI) in newborn rats. Seventy-two healthy SPF grade SD newborn rats were randomly and equally divided into Normal group (healthy rats) and Sham group (rats underwent sham operation), Model group (HIBI model rats), p38 MAPK Inhibitor group (HIBI model rats treated with p38 MAPK inhibitor) and p38 MAPK Activator group (HIBI model rats treated with p38 MAPK activator). On postnatal day 28, Morris water maze, tail suspension test and inclined plane test were conducted on rats in each group. Twenty-four hours after modeling, the expression of p-p38 MAPK protein and apoptosis related genes in rat hippocampal tissues was detected by TUNEL staining, qRT-PCR and Western blot. Compared with Normal group, escape latency and inclined plane test time were prolonged, the number of passing through the platform and tail suspension time were reduced (all P < 0.05); Bax and Caspase-3 mRNA and protein expression levels and p-p38 MAPK protein level were increased, Bcl-2 mRNA level was decreased, and neuronal apoptosis proportion was increased in Model group (all P < 0.05). Compared with Model group, the above indicators showed reversed and enhanced trends in p38 MAPK Inhibitor and p38 MAPK Activator groups, respectively (all P < 0.05). Inhibition of p38 MAPK signaling pathway can effectively improve the learning and memory ability and motor function of newborn rats with HIBI, and reduce neuronal apoptosis in the hippocampal tissues, thereby promoting neuronal recovery.


Assuntos
Apoptose , Cognição/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/fisiopatologia , Neurônios/fisiologia , Recuperação de Função Fisiológica , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Neurotoxicology ; 67: 150-160, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29860053

RESUMO

Due to their extremely small size that gives them unique physicochemical properties, nanoparticles (NPs) are used in the production of everyday materials. However, NPs can accumulate in body organs and could cause various diseases. Moreover, NPs that cross biological membranes such as the blood-brain barrier can aggregate in the brain and potentially produce neuronal damage. Although studies have reported the effects of diverse NPs on the bioelectrical properties of individual neurons, their potential influences on the operation of whole neuronal networks have not been documented. Here, we aimed to evaluate the effects of an acute exposure to zinc oxide (ZnO) NPs on the central neural networks responsible for mammalian respiratory rhythm generation. Using an isolated ex vivo brainstem-spinal cord preparation from neonatal rat in which the circuitry for the central respiratory command remained intact, we show that ZnO NPs accelerate, then profoundly disrupt respiratory-related activity produced by the pre-Bötzinger complex (preBötC) responsible for inspiratory rhythm generation. Consequently, a sudden and definitive cessation of respiratory-related activity occurs in ZnO NPs-exposed preparations. Part of these effects is related to zinc ions released from NPs. Using brainstem slice preparations containing the preBötC network, whole-cell patch-clamp recordings revealed that ZnO NPs depolarize preBötC inspiratory neurons and affect their bioelectrical properties by reducing the amplitude of action potentials, thereby leading to a depression of intra-network activity and the ultimate termination of respiratory rhythmogenesis. These findings support the conclusion that ZnO NPs may have deleterious effects on the central respiratory centers of newborn mammals.


Assuntos
Nanopartículas/toxicidade , Rede Nervosa/efeitos dos fármacos , Centro Respiratório/efeitos dos fármacos , Protetores Solares/toxicidade , Óxido de Zinco/toxicidade , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Feminino , Masculino , Nanopartículas/administração & dosagem , Rede Nervosa/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Centro Respiratório/fisiologia , Protetores Solares/administração & dosagem , Óxido de Zinco/administração & dosagem
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