RESUMO
The therapeutic activities of curcumin have long been investigated in some chronic and inflammatory diseases. This study was designed to investigate the protective effects of nanocurcumin on intestinal barrier function, apoptosis, and oxidative stress in rats exposed to traffic noise. Forty rats were divided into four groups: two traffic noise-exposed groups of animals that received either vehicle (NOISE) or nanocurcumin (NCUR + NOISE) and two control groups that either remained intact (CON) or received nanocurcumin (NCUR). Nanocurcumin injection (15 mg/Kg/ip) and traffic noise exposure were administered daily for two weeks. The relative protein expression of intestinal tight junctions, occludin, and ZO-1 and Bax/Bcl-2 ratio was measured to evaluate barrier integrity and apoptosis in intestinal samples, respectively. Plasma D-lactate concentration was examined as a criterion of intestinal permeability. Corticosterone, superoxide dismutase (SOD) activity, glutathione (GSH), total antioxidant capacity (TAC), and nitrite were measured in serum. The noise exposure increased Bax/Bcl-2 ratio, corticosterone, and oxidative stress in the NOISE animals. Nanocurcumin treatment improved the Bax/Bcl-2 ratio and reduced corticosterone and oxidative stress in the NCUR + NOISE animals. The expression of tight junction proteins was decreased while the concentration of D-lactate was increased in the NOISE animals. Nanocurcumin did not efficiently impact the expression of tight junction proteins and the D-lactate level in the NCUR + NOISE group. Nanocurcumin administration displayed antioxidant and anti-apoptotic roles in the noise-exposed rats, however, it did not affect the intestinal barrier integrity. We concluded that reduced apoptosis in the intestine might be related to the antioxidant activity of nanocurcumin and its modulatory effects on the HPA axis in the nanocurcumin-treated animals.
Assuntos
Antioxidantes , Corticosterona , Curcumina , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Apoptose , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia , Corticosterona/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Intestinos , Lactatos/farmacologia , Estresse Oxidativo , Sistema Hipófise-Suprarrenal/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Estresse Psicológico , Proteínas de Junções Íntimas/metabolismo , Curcumina/farmacologia , NanomedicinaRESUMO
Multiple neuronal injury pathways are activated during cerebral ischemia and reperfusion (I/R). This study was designed to decrease potential neuronal injuries by using both transcranial direct current stimulation (tDCS) polarities in cerebral ischemia and its following reperfusion period. Ninety rats were randomly divided into six groups. In the sham group, rats were intact. In the I/R group, global cerebral I/R was only induced. In the I/R + c-tDCS and I/R + a-tDCS groups, cathodal and anodal currents were applied, respectively. In the I/R + c/a-tDCS, cathodal current was used in the cerebral ischemia and anodal in the reperfusion. In the I/R + a/c-tDCS group, cathodal and anodal currents were applied in the I/R, respectively. Hippocampal tissue was used to determine the levels of IL-1ß, TNF-α, NOS, SOD, MDA, and NMDAR. Hot plate and open field tests evaluated sensory and locomotor performances. The cerebral edema was also measured. Histological assessment was assessed by H/E and Nissl staining of the hippocampal CA1 region. All tDCS modes significantly decreased IL-1ß and TNF-α levels, especially in the c/a-tDCS. All tDCS caused a significant decrease in MDA and NOS levels while increasing SOD activity compared to the I/R group, especially in the c/a-tDCS mode. In the c-tDCS and a/c-tDCS groups, the NMDAR level was significantly decreased. The c/a-tDCS group improved sensory and locomotor performances more than other groups receiving tDCS. Furthermore, the least neuronal death was observed in the c/a-tDCS mode. Using two different polarities of tDCS could induce more neuroprotective versus pathophysiological pathways in cerebral I/R, especially in c/a-tDCS mode. HIGHLIGHTS: Multiple pathways of neuronal injury are activated in cerebral ischemia and reperfusion (I/R). Using tDCS could modulate neuroinflammation and oxidative stress pathways in global cerebral I/R. Using c/a-tDCS mode during cerebral I/R causes more neuroprotective effects against neuronal injuries of cerebral I/R.
Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Estimulação Transcraniana por Corrente Contínua , Animais , Isquemia Encefálica/terapia , Infarto Cerebral , Ratos , Reperfusão , Traumatismo por Reperfusão/terapia , Superóxido Dismutase , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Global cerebral ischemia (CI) causes severe neuronal injury, mainly in the hippocampal CA1 region. This study aimed to investigate an immediate using transcranial direct current stimulation (tDCS) in reducing neuronal injury induced by CI. MATERIALS AND METHODS: The 32 Wistar male rats were randomly divided into four groups (n=8 per group). In the ischemia group (I), CI was induced via the 4-vessel occlusion model. In the sham group (Sh), rats did not receive any intervention. In the ischemia+cathodal group (I+c/tDCS), the cathodal current was applied during CI. In the ischemia+anodal group (I+a/tDCS), the anodal current was applied. The current intensity of 400 µA was applied for 15-min during the ischemia. Hippocampal tissue was used to assess levels of NMDAR, IL-1ß, TNF-α, MDA, SOD, NOS, and apoptosis markers. Histological assessment and TUNEL staining were performed in CA1 hippocampal region. RESULTS: The c/tDCS significantly decreased the levels of IL-1ß and TNF-α than the I and a/tDCS groups. The c/tDCS significantly reduced MDA and NOS levels, while increasing the level of SOD than the I and a/tDCS. The c/tDCS caused a significant decrease in NMDAR level than the a/tDCS. Using c/tDCS significantly reduced the Bax and Caspase-3 expressions, while increasing the Bcl-2 expression than the I group. In the c/tDCS group, DNA fragmentation and neuronal death were significantly lower than the I and a/tDCS groups. CONCLUSION: Using cathodal a direct current could attenuate primary pathophysiological pathways induced by CI, and it eventually reduced neurons death and apoptosis in the CA1 hippocampal region.
Assuntos
Isquemia Encefálica , Região CA1 Hipocampal , Estimulação Transcraniana por Corrente Contínua , Animais , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , Região CA1 Hipocampal/fisiopatologia , Masculino , Neuroproteção , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
OBJECTIVES: We have previously shown that high-frequency (HF) deep brain stimulation (DBS) of the lateral hypothalamus (LH) during the acquisition phase of morphine-induced conditioned place preference (CPP) abolished the development of morphine reward. In the present study, we investigated the effect of DBS in the LH during the extinction phase of morphine CPP. MATERIALS AND METHODS: Rats were implanted with electrodes in the LH and went through conditioning trials for morphine CPP (40 min each, for three days), followed by extinction trials (20 min, for nine days). DBS-like stimulation (square pulses at 13 or 130 Hz, 200 µA, 100 µsec) was applied during the extinction trials. RESULTS: Rats that received HF-DBS (130 Hz) accomplished extinction of morphine place preference by day 5 of the phase, whereas those in sham-stimulation or low-frequency-DBS (LF-DBS, 13 Hz) groups reached the criterion for extinction at day 8. One day later, rats received a priming injection of morphine (2 mg/kg) to reinstate the extinguished preference. While rats in the sham-DBS and LF-DBS relapsed into the state of preferring morphine-associated context, those in the HF-DBS group did not show such preference. Rats were then proceeded into an additional phase of extinction training (20 min, once daily, three to five days) with DBS, followed by restraint stress-induced reinstatement test. Again, sham-DBS and LF-DBS had no effect on relapse to the morphine place preferring state, but HF-DBS completely prevented the relapse. CONCLUSION: HF-DBS facilitated extinction of morphine place preference and disrupted drug priming- and stress-induced renewal of morphine place preference.
Assuntos
Estimulação Encefálica Profunda , Preparações Farmacêuticas , Animais , Extinção Psicológica , Região Hipotalâmica Lateral , Morfina , RatosRESUMO
BACKGROUND: Hippocampal aromatase is responsible for local synthesis of 17ß-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. METHOD: Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. RESULTS: Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 µg. Letrozole also caused an up-regulation of ERα and ERß and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals. CONCLUSION: The detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.
Assuntos
Inibidores da Aromatase/farmacologia , Cognição/efeitos dos fármacos , Estradiol/biossíntese , Hipocampo/efeitos dos fármacos , Letrozol/farmacologia , Células Piramidais/efeitos dos fármacos , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva , Teste de Labirinto em Cruz Elevado , Estradiol/sangue , Estradiol/metabolismo , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/genética , Feminino , Hipocampo/metabolismo , Injeções Intraventriculares , Masculino , Teste de Campo Aberto , Orquiectomia , Ovariectomia , Células Piramidais/metabolismo , Ratos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Análise de Célula ÚnicaRESUMO
The orbitofrontal cortex (OFC) is involved in compulsive drug seeking and drug relapse. Its involvement in cue-, context-, and stress-induced reinstatement of drug seeking has also been confirmed in animal models. Deep brain stimulation (DBS) was proposed to be an effective intervention for patients with treatment-refractory addiction. Therefore, in the present study, we investigated the potential efficacy of DBS in the OFC for controlling addictive-like behaviors in rats. Rats were bilaterally implanted with electrodes in the OFC and trained to the morphine conditioned place preference (CPP; 3, 5, and 7 mg/kg). High-frequency (HF; 130 Hz) or low-frequency (LF; 13 Hz) DBS-like stimulation was applied during the conditioning (40 minutes, once daily, 3 days) or extinction (20 minutes, once daily, 6-10 days) trials. Following the extinction, morphine preference was reinstated by a priming dose of morphine (2 mg/kg). When applied during the conditioning phase, HF-DBS significantly decreased preference for the morphine-associated context. HF-DBS during the extinction phase of morphine CPP reduced the number of days to full extinction of morphine preference and prevented morphine priming-induced recurrence of morphine preference. LF-DBS did not change any of these addictive behaviors. HF-DBS had no significant effect on novel object recognition memory. In conclusion, HF-DBS of the OFC prevented morphine preference, facilitated extinction of morphine preference, and blocked drug priming-induced reinstatement of morphine seeking. These findings may indicate a potential applicability of DBS in the treatment of relapse to drug use. Further studies will be necessary to assess the translatability of these findings to the clinic.
Assuntos
Analgésicos Opioides/farmacologia , Comportamento Animal , Estimulação Encefálica Profunda/métodos , Comportamento de Procura de Droga , Morfina/farmacologia , Córtex Pré-Frontal , Animais , Condicionamento Clássico , Extinção Psicológica , Masculino , Dependência de Morfina , RatosRESUMO
Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100-microsecond pulse duration and 150 µA) was applied during the morphine-pairing trials (30 minutes daily for 4 days) or drug-free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.
Assuntos
Comportamento Animal , Condicionamento Clássico , Estimulação Encefálica Profunda/métodos , Região Hipotalâmica Lateral , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Reforço Psicológico , Anedonia , Animais , Comportamento Exploratório , Motivação , Ratos , Recompensa , Sacarose , EdulcorantesRESUMO
Accumulating evidence indicated that minocycline, a glial cell modulator, is able to modify a variety of morphine effects. Here, we investigated minocycline effects on electrical activity of nucleus accumbens (NAc) neurons using single unit recording in urethane-anesthetized rats. In addition, we investigated whether minocycline can modify the effects of morphine on NAc neural activity during reinstatement of morphine-seeking behavior. Minocycline increased the NAc firing activity in intact animals. Electrophysiological recording in morphine-treated animals was performed, following the acquisition of morphine-induced conditioned place preference (5 mg/kg, s.c., 3 days) and a drug-free extinction period. In acutely minocycline- treated animals, the neurons were recorded for 40 minutes following a single injection of either minocycline (50 µg/5 µl, i.c.v.) or saline. Then a priming dose of morphine (1 mg/kg, s.c.) was injected while the recording was continued for an additional 40 minutes. Minocycline significantly increased the firing rates of neurons and significantly modified morphine inhibitory effects on NAc neurons. In subchronically minocycline-treated groups, the rats were given daily injections of minocycline (50 µg/5 µl, i.c.v) during the extinction period. Then, on the reinstatement day, NAc neurons were recorded for 10 minutes, the priming dose of morphine was administered and the recording was continued for 45 minutes. Our results showed the failure of minocycline to significantly modify the inhibitory effects of morphine. In conclusion, our findings indicated that minocycline modifies morphine-induced decreases in the firing rates of NAc neurons in the reinstatement phase.
Assuntos
Minociclina/farmacologia , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Antibacterianos/farmacologia , Condicionamento Clássico , Modelos Animais de Doenças , Comportamento de Procura de Droga/efeitos dos fármacos , Eletrodiagnóstico/métodos , Masculino , Dependência de Morfina/prevenção & controle , Ratos , Ratos WistarRESUMO
PRIMARY OBJECTIVE: To assess the demographics, causes, treatment and outcome of traumatic brain injury (TBI) in Tehran, Iran. RESEARCH DESIGN AND METHODS: This retrospective study was conducted in a major trauma centre in south of Tehran using clinical data registry of 3818 traumatic patients who admitted to the hospital from 2009 to 2013. The main factors measured were the external cause of trauma, the type of TBI, and treatment outcome. MAIN OUTCOMES AND RESULTS: The highest rate of TBIs occurred in age categories 21â30 (31.5%), 31â40 (19.2%) and 41â50 (12.3%) years. Transport accidents were the most common cause of TBIs (2915 cases, 76.4%). The most frequent types of head injuries were subarachnoid (1676, 43.9%) subdural (1140, 29.8%), and epidural haemorrhage (974, 25.5%). A binomial logistic regression showed that mortality (612 patients, 16%) was significantly associated with the external cause of TBI, the type of main and additional head injuries, cervical spine injury, intra-abdominal organ injury, having a brain or abdominal surgery, and length of hospital stay. CONCLUSION: The mechanism of TBI, the type of head injuries, and accompanying spine and abdominal injuries were significant prognostic factors in traumatic patients.
Assuntos
Lesões Encefálicas Traumáticas/epidemiologia , Adulto , Distribuição por Idade , Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Feminino , Cabeça/patologia , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: A detrimental effect of commonly used anesthetics on the neurodevelopmental and behavioral parameters has long been shown in young animals subjected to early childhood anesthesia. Epidemiologic studies suggest the possibility of a modestly elevated risk of adverse neurodevelopmental outcomes in children exposed to anesthesia during early childhood. However, these results are still preliminary and inconclusive. AIM: To further elucidate the probability of occurrence of such adverse outcomes, we evaluated cognitive performance of children who underwent general anesthesia early in their childhood. METHOD: One hundred and fifteen children aged 5-16 years with established glaucoma were included in the study. Of these, 68 children had a history of at least one general anesthesia with sevoflurane before age 3. Phonemic and semantic verbal fluency, and forward and backward digit span tests were performed to evaluate cognitive function in the study subjects. RESULTS: The two-way anova revealed that all these variables showed significant changes in various age groups, but they were comparable among subjects with no, single, or multiple childhood anesthesia. CONCLUSION: It can be concluded that brief periods of anesthesia with single anesthetic sevoflurane may be safe for children under age 3.
Assuntos
Anestésicos Inalatórios/efeitos adversos , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Éteres Metílicos/efeitos adversos , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Retrospectivos , SevofluranoRESUMO
The hippocampus receives sparse orexinergic innervation from the lateral hypothalamus and expresses a high level of orexin receptor. The function of orexin receptor in the regulation of hippocampal neural activity has never been investigated. In this study, in vivo single unit recording was performed in urethane-anesthetized rats. After 15 min of baseline recording from pyramidal neuron within the CA1 region of the dorsal hippocampus, i.c.v. injection of orexin-A 0.5 nmol, SB334867 400 nmol, a selective orexin receptor 1 antagonist, saline, or DMSO, or microinjection of carbachol 250 nmol or saline into the ipsilateral lateral hypothalamus were performed using a Hamilton microsyringe, and the spontaneous firing activity continued to be recorded for 25 min. Results showed that orexin administration into the lateral cerebral ventricle excited 6 out of 8 neurons and inhibited 1 neuron. Chemical stimulation of the lateral hypothalamus by carbachol excited 9 out of 13 hippocampal neurons and inhibited 3 neurons. On the other hand, i.c.v. injection of the SB334867, caused reductions in the firing activity of 6 out of 10 neurons and increases in 4 additional neurons. It seems that orexin neurotransmission in the hippocampus mostly elicits an excitatory response, whereas blockade of orexin receptor has an inhibitory effect. Further studies need to be done to elucidate the underlying mechanism of orexin action on hippocampal neurons.
Assuntos
Hipocampo/fisiologia , Região Hipotalâmica Lateral/fisiologia , Receptores de Orexina/fisiologia , Orexinas/fisiologia , Células Piramidais/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Benzoxazóis/administração & dosagem , Carbacol/administração & dosagem , Hipocampo/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Infusões Intraventriculares , Masculino , Naftiridinas , Antagonistas dos Receptores de Orexina , Orexinas/administração & dosagem , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Ureia/administração & dosagem , Ureia/análogos & derivadosRESUMO
Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.
Assuntos
Acetilcisteína , Morfina , Humanos , Ratos , Animais , Morfina/farmacologia , Acetilcisteína/farmacologia , Ratos Wistar , Extinção Psicológica/fisiologia , Núcleo Accumbens , NeurôniosRESUMO
Introduction: & Objective: Cerebral ischemia/reperfusion (I/R) injury, the second cause of death globally, involves increased NMDA receptor activity leading to neuronal damage due to excessive sodium and calcium ion entry. Therefore, targeting NMDA receptor may potentially reduce cell death induced by brain injury. Our study aimed to investigate the role of NMDA receptors in hippocampal neuronal activity induced by I/R. Methods: In this study, Wistar rats were divided into four groups: sham, I/R, I/R + MK801, and I/R + NMDA. Cerebral I/R injury was induced by temporarily occluding the common and vertebral carotid arteries, followed by reperfusion. MK801 or NMDA was administered to the rats after a specific reperfusion time. Neuronal density and cell morphology in the hippocampal CA1 region were assessed using Nissl and H&E staining. The expression of BDNF, p-CREB, and c-fos was evaluated through Western blot analysis. Additionally, neuronal activity in CA1 pyramidal neurons were examined using single unit recording technique. Results: Our results showed that cerebral I/R injury caused significant damage to CA1 pyramidal neurons compared to the sham group. However, treatment with MK-801 improved hippocampal cell survival compared to the I/R group. Furthermore, MK-801 administration in I/R rats increased BDNF, c-fos, and p-CREB levels while decreasing cleaved caspase-3 activity compared to the I/R group. Additionally, electrophysiological data showed that MK-801 increased firing rates of CA1 pyramidal neurons during the reperfusion phase. Conclusion: MK-801 shows promise as a therapeutic agent for cerebral I/R injury by enhancing cell survival, upregulating neuroplasticity factors, and increasing firing rates of CA1 pyramidal neurons. It exerts a specific protective effect against cerebral I/R injury.
RESUMO
In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Recompensa , Animais , Proteína de Ligação a CREB/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND & OBJECTIVES: Accurate and rapid diagnosis of acute myocardial infarction (MI) is of major clinical significance. The troponin is the biomarker of choice for detection of cardiac injury. The objective of this study was to identify salivary levels of cardiac troponin I (cTnI) in patients with acute MI. METHODS: Thirty patients with acute MI and 28 normal healthy individuals were included in the study. cTnI levels were assayed in serum and saliva 12 and 24 h of acute MI by ELISA method. RESULTS: In patients with acute MI, the serum and resting (unstimulated) saliva concentrations of cTnI, but not stimulated saliva cTnI, at both 12 and 24 h of onset of MI, were significantly higher than in controls. Resting saliva cTnI concentrations correlated significantly with serum cTnI levels (spearman rho = 0.34 and 0.45 in the total individuals and in the MI patients respectively). INTERPRETATION & CONCLUSIONS: The present results suggest that saliva can be an analytical matrix for measurement of cTnI in patients with acute MI. Further studies may reveal capability of salivary cTnI for being used for developing point-of-care testing for early detection of MI in pre-clinical settings.
Assuntos
Diagnóstico Precoce , Infarto do Miocárdio/diagnóstico , Saliva/metabolismo , Troponina I , Adulto , Idoso , Biomarcadores , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Troponina I/sangueRESUMO
It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.
Assuntos
Estimulação Encefálica Profunda , Região Hipotalâmica Lateral , Masculino , Animais , Ratos , Região Hipotalâmica Lateral/fisiologia , Morfina/farmacologia , Estimulação Encefálica Profunda/métodos , Ratos Wistar , RecompensaRESUMO
Methamphetamine (METH) addiction is a significant public health issue, and standard medical therapies are often not curative. Deep Brain Stimulation (DBS) has recently shown the potential to cure addiction by modulating neural activity in specific brain circuits. Recent studies have revealed that the nucleus accumbens shell (NAcSh) could serve as a promising target in treating addiction. Therefore, the present study aimed to investigate the therapeutic effects of NAcSh high- or low-frequency stimulation (HFS or LFS) in the different time points of application on the extinction and reinstatement of the METH-conditioned place preference (CPP). LFS or HFS (10 or 130 Hz, 150-200 µA, 100 µs) was delivered to the NAcSh for 30 min non-simultaneous (in a distinct non-drug environment) or simultaneous (in a drug-paired context) of the drug-free extinction sessions. The obtained results showed that both non-simultaneous and simultaneous treatments by HFS and LFS notably reduced the extinction period of METH-induced CPP. Furthermore, the data indicated that both non-synchronous and synchronous HFS prevented METH-primed reinstatement, while only the LFS synchronized group could block the reinstatement of METH-seeking behavior. The results also demonstrated that HFS was more effective than LFS in attenuating METH-primed reinstatement, and applying HFS synchronous was significantly more effective than HFS non-synchronous in reducing the relapse of drug-seeking. In conclusion, the current study's results suggest that DBS of the NAcSh in a wide range of frequencies (LFS and HFS) could affect addiction-related behaviors. However, it should be considered that the frequency and timing of DBS administration are among the critical determining factors.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Estimulação Encefálica Profunda , Metanfetamina , Ratos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Núcleo Accumbens , Estimulação Encefálica Profunda/métodos , Condicionamento Operante , Extinção Psicológica , Transtornos Relacionados ao Uso de Anfetaminas/terapiaRESUMO
AIMS: The orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats. MAIN METHODS: Electrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high- or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg). KEY FINDINGS: The HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. SIGNIFICANCE: Conclusively, DBS administration in the OFC demonstrated some positive results, including suppressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.
Assuntos
Estimulação Encefálica Profunda , Metanfetamina , Ratos , Animais , Estimulação Encefálica Profunda/métodos , Condicionamento Operante , Extinção Psicológica , Córtex Pré-Frontal , RecidivaRESUMO
We have previously shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) compromises morphine-induced addiction-like behavior in rats. The exact mechanism underlying this effect is not known. Here, we investigated the assumption that DBS in the LH influences the firing activity of neurons in the ventral tegmental area (VTA). To that end, male Wistar rats received morphine (5 mg/kg; s.c.) for three days and underwent extracellular single unit recording under general anesthesia one day later. During the recording, the rats received an intraoperative injection of morphine (5 mg/kg; s.c.) plus DBS in the LH (130 Hz pulse frequency, 150 µA amplitude, and 100 µs pulse width). One group of animals also received preoperative DBS after each morphine injection before the recording. The spiking frequency of VTA neurons was measured at three successive phases: (1) baseline (5-15 min); (2) DBS-on (morphine + DBS for 30 min); and (3) After-DBS (over 30 min after termination of DBS). Results showed that morphine suppressed the firing activity of a large population of non-DA neurons, whereas it activated most DA neurons. Intraoperative DBS reversed morphine suppression of non-DA firing, but did not alter the excitatory effect of morphine on DA neurons firing. With repeated preoperative application of DBS, non-DA neurons returned to the morphine-induced suppressive state, but DA neurons released from the excitatory effect of morphine. It is concluded that the development of morphine reward is associated with a hypoactivity of VTA non-DA neurons and a hyperactivity of DA neurons, and that DBS modulation of the spiking activity may contribute to the blockade of morphine addiction-like behavior.