RESUMEN
Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.
Asunto(s)
Astrocitos , Disfunción Cognitiva , Hipocampo , Lipocalina 2 , Potenciación a Largo Plazo , Enfermedades Neuroinflamatorias , Neuronas , Animales , Astrocitos/metabolismo , Astrocitos/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Lipocalina 2/metabolismo , Lipocalina 2/genética , Ratones , Hipocampo/metabolismo , Hipocampo/patología , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones Noqueados , Masculino , Ratones Endogámicos C57BL , Receptores de N-Metil-D-Aspartato/metabolismo , Optogenética , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/metabolismo , Modelos Animales de EnfermedadRESUMEN
Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage-dependent Na⁺ channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin-resistant (TTX-R) Na⁺ channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na⁺ currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na⁺ currents, it strongly inhibited steady-state currents of transient as well as persistent Na⁺ currents in a concentration-dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na⁺ channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na⁺ channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na⁺ currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches.
Asunto(s)
Animales , Ratas , Potenciales de Acción , Anticonvulsivantes , Carbamazepina , Cefalea , Cinética , Trastornos Migrañosos , Enfermedades del Sistema Nervioso , Neuronas , Neuronas Aferentes , Canales de Sodio , Ganglio del TrigéminoRESUMEN
<p><b>OBJECTIVES</b>The demand for mobile bathing service (MBS) is increasing in the Japanese society. Therefore, we assessed the risk of MBS-associated infection in MBS clients and their caregivers by examining the bacterial colonization of MBS equipment and utensils.</p><p><b>METHODS</b>Bacterial isolates collected by the stamp agar culture method were examined by disk diffusion assay for their susceptibility to the following drugs: imipenem, ciprofloxacin, amikacin, azutreonam, ceftazidim, meropenem, piperacillin, tobramycin, ofloxacin and cefoperazone. Furthermore, these isolates were subtyped bySpeI-pulsed field gel electrophoresis (SpeI-PFGE).</p><p><b>RESULTS</b>Fifty-fourP. aeruginosa isolates were recovered from different sampling sites, and of these, 26 (47.3%) were isolated from pillows. Eighteen isolates (33.3%) were imipenem (IPM) resistant. The minimum inhibitory concentrations (MICs) of 17 isolates were between 16 and 32 μg/ml, and the MIC of one isolate was greater than 32 μg/ml. TheSpeI-PFGE typing of IPM-resistant isolates revealed that 13 of the 18 isolates were closely related (F=1.0-0.87).</p><p><b>CONCLUSION</b>Our findings suggest that MBS equipment and utensils, particularly pillows, are the primary sources of bacterial contamination and transmission and that there is a risk of MBS-mediated infection among MBS clients and their caregivers.</p>
RESUMEN
Objectives: The demand for mobile bathing service (MBS) is increasing in the Japanese society. Therefore, we assessed the risk of MBS-associated infection in MBS clients and their caregivers by examining the bacterial colonization of MBS equipment and utensils. Methods: Bacterial isolates collected by the stamp agar culture method were examined by disk diffusion assay for their susceptibility to the following drugs: imipenem, ciprofloxacin, amikacin, azutreonam, ceftazidim, meropenem, piperacillin, tobramycin, ofloxacin and cefoperazone. Furthermore, these isolates were subtyped by SpeI-pulsed field gel electrophoresis (SpeI-PFGE). Results: Fifty-four P. aeruginosa isolates were recovered from different sampling sites, and of these, 26 (47.3%) were isolated from pillows. Eighteen isolates (33.3%) were imipenem (IPM) resistant. The minimum inhibitory concentrations (MICs) of 17 isolates were between 16 and 32 μg/ml, and the MIC of one isolate was greater than 32 μg/ml. The SpeI-PFGE typing of IPM-resistant isolates revealed that 13 of the 18 isolates were closely related (F=1.0−0.87). Conclusion: Our findings suggest that MBS equipment and utensils, particularly pillows, are the primary sources of bacterial contamination and transmission and that there is a risk of MBS-mediated infection among MBS clients and their caregivers.