Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis / Isoflurano fornece neuroproteção em lesão cerebral hipóxico-isquêmica neonatal por inibição da apoptose

Abstract Background and objectives: Isoflurane is halogenated volatile ether used for inhalational anesthesia. It is widely used in clinics as an inhalational anesthetic. Neonatal hypoxic ischemia injury ensues in the immature brain that results in delayed cell death via excitotoxicity and oxidative stress. Isoflurane has shown neuroprotective properties that make a beneficial basis of using isoflurane in both cell culture and animal models, including various models of brain injury. We aimed to determine the neuroprotective effect of isoflurane on hypoxic brain injury and elucidated the underlying mechanism. Methods: A hippocampal slice, in artificial cerebrospinal fluid with glucose and oxygen deprivation, was used as an in vitro model for brain hypoxia. The orthodromic population spike and hypoxic injury potential were recorded in the CA1 and CA3 regions. Amino acid neurotransmitters concentration in perfusion solution of hippocampal slices was measured. Results: Isoflurane treatment caused delayed elimination of population spike and improved the recovery of population spike; decreased frequency of hypoxic injury potential, postponed the onset of hypoxic injury potential and increased the duration of hypoxic injury potential. Isoflurane treatment also decreased the hypoxia-induced release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but the levels of γ-aminobutyric acid were elevated. Morphological studies showed that isoflurane treatment attenuated edema of pyramid neurons in the CA1 region. It also reduced apoptosis as evident by lowered expression of caspase-3 and PARP genes. Conclusions: Isoflurane showed a neuro-protective effect on hippocampal neuron injury induced by hypoxia through suppression of apoptosis.

Resumo Justificativa e objetivos: Isoflurano é um éter volátil halogenado usado para anestesia por via inalatória. É amplamente usado na clínica como um anestésico para inalação. A lesão hipóxico-isquêmica neonatal ocorre no cérebro imaturo e resulta em morte celular tardia via excitotoxicidade e estresse oxidativo. Isoflurano mostrou ter propriedades neuroprotetoras que formam uma base benéfica para o seu uso tanto em cultura de células quanto em modelos animais, incluindo vários modelos de lesão cerebral. Nosso objetivo foi determinar o efeito neuroprotetor de isoflurano em hipóxia cerebral e elucidar o mecanismo subjacente. Métodos: Fatias de hipocampo, em fluido cerebrospinal artificial (CSFA) com glicose e privação de oxigênio, foram usadas como um modelo in vitro de hipóxia cerebral. O pico de população ortodrômica (PPO) e o potencial de lesão hipóxica (PLH) foram registrados nas regiões CA1 e CA3. A concentração de neurotransmissores de aminoácidos na solução de perfusão das fatias de hipocampo foi medida. Resultados: O tratamento com isoflurano retardou a eliminação do PPO e melhorou a recuperação do PPO; diminuiu a frequência do PLH, retardou o início do PLH e aumentou a duração do PLH. O tratamento com isoflurano também diminuiu a liberação de neurotransmissores de aminoácidos induzida pela hipóxia, como aspartato, glutamato e glicina, mas os níveis de ácido γ-aminobutírico (GABA) estavam elevados. Estudos morfológicos mostram que o tratamento de edema com isoflurano atenuou o edema de neurônios piramidais na região CA1. Também reduziu a apoptose, como mostrado pela expressão reduzida da caspase-3 e genes PARP. Conclusões: Isoflurano mostrou um efeito neuroprotetor na lesão neuronal no hipocampo induzida por hipóxia através da supressão de apoptose.

Translational realistic expectations of chronic cerebral hypoxemia in rat model after bilateral commom carotid artery ligation. Neurocognitive aspects

To evaluate the effects of chronic cerebral hypoxia on memory of rats submitted to bilateral common carotid artery ligation (BCCL). METHODS: Every each week, for 16 weeks, 31 rats were tested for memory using a water and land mazes and compared with 30 normal rats (control group A). The variables were expressed by their mean and standard error of the mean (SEM). p<0.05 was used for rejecting the null hypothesis. The study was approved by the Ethics Committee for animal investigation. RESULTS: There was a significant increase in the latency time, in the survival water and land mazes, after four weeks (study group B) follow-up. However, without any medication or therapeutically induced measures, after 16 weeks (study group C) follow-up the latency mean times tend to be similar to control group (A) in the neurocognitive tests. CONCLUSIONS: Neurocognitive deficits after 16 weeks post-operative follow-up of rats that underwent bilateral common carotid artery ligation is a natural adaptive phenomenon. Thus, is not realistic to allow translational information from this animal model for therapeutically approaches aiming at to prevent, or to improve brain damage in human beings suffering from chronic deprivation of adequate blood supply.

Mitochondrial apoptotic signaling pathway in neurons following brain injury induced by hypoxia / 法医学杂志

Impairment of neuronal mitochondria following hypoxia of brain not only result in nerve cell's energy-deprivation and dysfunction, mitochondria also play key roles in apoptosis of neurons. A central step being the release of cytochrome c (cyt c) across the outer mitochondrial membrane into the cytoplasm through opening of the mitochondrial permeability transition pore. Releasing of cytochrome c induce to downstream consequences of specific caspase activation. The antiapoptotic and proapoptotic members of the Bcl-2 family regulate mitochondrial activities relevant to apoptotic signaling by influencing the realaseing of cyt c.

Aspectos relevantes de la encefalopatía hipóxico-isquémica / Hypoxic-ischemic encephalopaty aspects relevants

El seguimiento del embarazo, la atención del parto y la reanimación del recién nacido, exigen la detección oportuna y el tratamiento adecuado del sufrimiento cerebral debido a la asfixia. Una vez que la lesión cerebral se establece, todos los esfuerzos estarán encaminados a disminuir sus consecuencias. La coordinación entre el obstetra y el pediatra, fundada en la confianza mutua, el profesionalismo y la experiencia de ambos favorece la toma de decisiones pertinentes, para otorgar al niño la posibilidad de preservar, en lo posible su evolución motora e intelectual