Physiologic roles of P2 receptors in leukocytes.

Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system, purinergic receptors participate in innate immunity and in the modulation of the adaptive immune response. In particular, P2 receptors, which respond to extracellular nucleotides, are widely expressed on leukocytes, causing the release of cytokines and chemokines and the formation of inflammatory mediators, and inducing phagocytosis, degranulation, and cell death. The activity of these receptors is regulated by ectonucleotidases-expressed in these same cell types-which regulate the availability of nucleotides in the extracellular environment. In this article, we review the characteristics of the main purinergic receptor subtypes present in the immune system, focusing on the P2 family. In addition, we describe the physiologic roles of the P2 receptors already identified in leukocytes and how they can positively or negatively modulate the development of infectious diseases, inflammation, and pain.

Modulation of cerebral haemodynamic response to olfactory stimuli by emotional valence detected by functional magnetic resonance imaging / Modulação da resposta hemodinâmica cerebral pela valência emocional de estímulos olfativos detectada pela por ressonância magnética funcional

ABSTRACT. Olfactory perception, although restricted to just a few contexts in everyday life, is key in medicine. Several dementia conditions have been associated with early loss of olfactory discrimination. Despite the fact that several brain areas have been associated with olfaction in functional magnetic resonance imaging (fMRI), the mechanisms by which emotional valence is conveyed to the brain are not fully understood. Methods. In this study, we compared cerebral activations by olfactory stimuli using different emotional valence stimuli on event-related fMRI. We used three standard olfactory odorants with different valence (positive, neutral and negative). Forty-three healthy subjects (22 males) were scanned on a 3.0T MR system. Olfactory stimulation was attained through a delivery system synchronized with image acquisition and subjects´ breathing instructions. fMRI data analysis was performed by the FSL package (Oxford University) including head movement correction, GLM modeling of the neurovascular (BOLD) response and group activation maps produced at p<0.05 and corrected for multiple comparison. Results. Increased cerebral responses within the anterior cingulate, amygdaloid nuclei, as well as the dorsolateral prefrontal, occipital and orbitofrontal cortices were observed in positive and negative valence conditions, while response to neutral valence arousal was less intense and not observed in the amygdaloid complex. The most significant statistical response aroused from the stimuli clusters was observed in the negative condition. Conclusion. The results of the present study support the hypothesis that neutral stimuli may be more sensitive to early losses in pathological conditions, particularly dementia.

RESUMO. Apesar de praticamente restrita a alguns contextos na rotina diária, a percepção de estímulos olfativos é bastante relevante em medicina. Várias condições patológicas, e em particular as demências, estão associadas à perda precoce da capacidade de discriminação e percepção olfativa. Apesar de estudos de ressonância magnética funcional (RMf), terem identificado várias áreas cerebrais relacionadas à percepção olfativa, ainda não sabemos quais destas são moduladas pela valência emocional do estímulo olfativo. Neste estudo investigamos o padrão de resposta cerebral à odorantes com diferentes valências emocionais em indivíduos saudáveis estudados por RMf relacionada à eventos. Métodos. Comparamos a resposta cerebral em um desenho de RMf relacionado à eventos e com uso de três estímulos olfatórios padronizados e com diferentes valências emocionais (positiva, neutra e negativa). Quarenta e três indivíduos normais (22 homens) foram estudados por RMf relacionada à eventos em aparelho de 3T. A estimulação olfativa foi realizada por meio de sistema sincronizado à aquisição das imagens e às instruções dadas aos sujeitos. A análise dos dados foi feita por meio do software FSL (Universidade de Oxford) e incluiu correções de movimento, modelagem de sinal com técnica GLM e mapas de grupo com nível de significância < 0,5. Resultados. As respostas cerebrais no cíngulo anterior, bem como no córtex dorsolateral pré-frontal, occipital e órbitofrontal foram observadas nas condições de valência positiva e negativa, porém a resposta ao estímulo neutro foi menos intensa e não foi observada em complexos amigdaloides. A resposta estatística mais significante foi observada no cluster de estímulos com valência negativa. Conclusão. Estes dados representam evidências para a hipótese de que possivelmente a perda da percepção discriminativa de estímulos com valência emocional neutra pode ser mais sensível em relação às manifestações iniciais de condições patológicas, inclusive demências.

Modulation of cerebral haemodynamic response to olfactory stimuli by emotional valence detected by functional magnetic resonance imaging.

Olfactory perception, although restricted to just a few contexts in everyday life, is key in medicine. Several dementia conditions have been associated with early loss of olfactory discrimination. Despite the fact that several brain areas have been associated with olfaction in functional magnetic resonance imaging (fMRI), the mechanisms by which emotional valence is conveyed to the brain are not fully understood. METHODS: In this study, we compared cerebral activations by olfactory stimuli using different emotional valence stimuli on event-related fMRI. We used three standard olfactory odorants with different valence (positive, neutral and negative). Forty-three healthy subjects (22 males) were scanned on a 3.0T MR system. Olfactory stimulation was attained through a delivery system synchronized with image acquisition and subjects´ breathing instructions. fMRI data analysis was performed by the FSL package (Oxford University) including head movement correction, GLM modeling of the neurovascular (BOLD) response and group activation maps produced at p<0.05and corrected for multiple comparison. RESULTS: Increased cerebral responses within the anterior cingulate, amygdaloid nuclei, as well as the dorsolateral prefrontal, occipital and orbitofrontal cortices were observed in positive and negative valence conditions, while response to neutral valence arousal was less intense and not observed in the amygdaloid complex. The most significant statistical response aroused from the stimuli clusters was observed in the negative condition. CONCLUSION: The results of the present study support the hypothesis that neutral stimuli may be more sensitive to early losses in pathological conditions, particularly dementia.

Apesar de praticamente restrita a alguns contextos na rotina diária, a percepção de estímulos olfativos é bastante relevante em medicina. Várias condições patológicas, e em particular as demências, estão associadas à perda precoce da capacidade de discriminação e percepção olfativa. Apesar de estudos de ressonância magnética funcional (RMf), terem identificado várias áreas cerebrais relacionadas à percepção olfativa, ainda não sabemos quais destas são moduladas pela valência emocional do estímulo olfativo. Neste estudo investigamos o padrão de resposta cerebral à odorantes com diferentes valências emocionais em indivíduos saudáveis estudados por RMf relacionada à eventos. MÉTODOS: Comparamos a resposta cerebral em um desenho de RMf relacionado à eventos e com uso de três estímulos olfatórios padronizados e com diferentes valências emocionais (positiva, neutra e negativa). Quarenta e três indivíduos normais (22 homens) foram estudados por RMf relacionada à eventos em aparelho de 3T. A estimulação olfativa foi realizada por meio de sistema sincronizado à aquisição das imagens e às instruções dadas aos sujeitos. A análise dos dados foi feita por meio do software FSL (Universidade de Oxford) e incluiu correções de movimento, modelagem de sinal com técnica GLM e mapas de grupo com nível de significância < 0,5. RESULTADOS: As respostas cerebrais no cíngulo anterior, bem como no córtex dorsolateral pré-frontal, occipital e órbitofrontal foram observadas nas condições de valência positiva e negativa, porém a resposta ao estímulo neutro foi menos intensa e não foi observada em complexos amigdaloides. A resposta estatística mais significante foi observada no cluster de estímulos com valência negativa. CONCLUSÃO: Estes dados representam evidências para a hipótese de que possivelmente a perda da percepção discriminativa de estímulos com valência emocional neutra pode ser mais sensível em relação às manifestações iniciais de condições patológicas, inclusive demências.

Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models.

PURPOSE: Pentylenetetrazole (PTZ) and maximal electroshock (MES) models are often used to induce seizures in nonepileptic control animals or naive animals. Despite being widely used to screen antiepileptic drugs (AEDs), both models have so far failed to detect potentially useful AEDs for treating drug-resistant epilepsies. Here we investigated whether the acute induction of MES and PTZ seizures in epileptic rats might yield a distinct screening profile for AEDs. METHODS: Status epilepticus (SE) was induced in adult male Wistar rats by intraperitoneal pilocarpine injection (Pilo, 320 mg/kg, i.p.). One month later, controls or naive animals (Cont) that did not develop SE postpilocarpine (N-Epi) and pilocarpine-epileptic rats (Epi) received one of the following: phenobarbital (PB, 40 mg/kg), phenytoin (PHT, 50 mg/kg), or valproic acid (VPA, 400 mg/kg). Thirty min later the animals were challenged with either subcutaneous MES or PTZ (50 mg/kg, s.c.). RESULTS: VPA, PB, and PHT were able to prevent MES in all groups tested (Cont, N-Epi, and Epi groups), whereas for the PTZ model, only the Cont group (naive animals) had seizure control with the same AEDs. In addition, Epi and N-Epi groups when challenged with PTZ exhibited a higher incidence of severe seizures (scores IV-IX) and SE (p < 0.05, Fisher's exact test). CONCLUSIONS: Our findings suggest that the induction of acute seizures with PTZ, but not with MES, in animals pretreated with pilocarpine (regardless of SE induction) might constitute an effective and valuable method to screen AEDs and to study mechanisms involved in pharmacoresistant temporal lobe epilepsy (TLE).