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신생쥐에서 유발시킨 저산소 허혈 뇌손상에 대한 melatonin과 저체온치료 병용요법의 효과

The Effect of Combination Treatment of Melatonin and Hypothermia on Hypoxic-Ischemic Brain Injury in Neonatal Rats

김천수|박재현|이상락|이성룡
대한신생아학회 (THE KOREAN SOCIETY OF NEONATOLOGY)|2014.05|Neonatal medicine|제21권 제2호|pp. 129-137

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키워드

HypothermiaMelatoninHypoxia-ischemia

초록

목적: Melatonin은 송과샘에서 분비되는 호르몬으로, 여러 조직에 있어 다양한 약리작용을 나타낸다. 특히, melatonin은 우수한 항산화 효과와 신경 보호작용을 가진다고 알려져 있다. 저체온치료는 저산소 허혈 뇌손상에 적용되는임상 치료법이다. 이 연구는 저산소 허혈을 유발시킨 신생쥐에서 melatonin 및 저체온치료의 병합요법의 효과에대하여 알아보고자 하였다. 방법: 생후 7일된 쥐에 저산소 허혈을 유발하였고, 실험군은 vehicle군과 melatonin 단독투여군, vehicle 및 저체온치료병합요법군, melatonin 및 저체온치료의 병합요법군으로 나누었다. Melatonin은 30 mg/kg 용량으로 복강 내 주사하였는데, 저산소 허혈 손상 직후 및 24시간 경과 시점으로 구분해서 2차례 투여하였다. 저체온치료는 전신 냉각으로 27℃ 환경에서 3시간동안 시행하였다. 정상 대조군은 저산소 허혈 뇌손상을 유발하지 않은 sham 수술군으로 하였다. 수술 후 3일(P10), 1주 경과(P14) 및 4주 시점(P35)에서 실험쥐를 희생시켜서 뇌손상을 평가하였다. 결과: TTC 염색에서 vehicle 투여한 P10 실험쥐는 저산소 허혈로 인한 뇌경색이 대조군에 비해 현저하였다. 또한, H&E염색에서 P35 실험쥐는 손상측 뇌위축이 현저하였다. Melatonin이나 저체온치료 단독으로는 뇌의 경색이나 위축을 유의하게 억제하지 못하였으나, melatonin 및 저체온요법의 병합치료는 뇌손상을 줄이는 효과가 있었다. In situ zymography 및 TUNEL 염색, 면역형광법을 이용해서 뇌손상을 평가한 결과 오직 병합요법만이 신경 보호효과를 나타내었다. 결론: Melatonin은 저산소 허혈 뇌손상에 대하여 저체온치료의 신경 보호작용에 상승효과를 가지는 것으로 보인다.

Abstract

Purpose: Melatonin is a naturally occurring hormone produced by the pineal gland. Melatonin has many pharmacological effects in different tissues or organs. Melatoninis especially known to have antioxidant and neuroprotective effects. Hypothermia is atherapeutic tool against hypoxia-ischemia (HI) of the brain. This study examines theeffect of combined therapy using melatonin and hypothermia in neonatal rats with HI. Methods: Seven-day old rats were subjected to HI and randomized into four groups :vehicle, melatonin alone, vehicle and hypothermia, and melatonin and hypothermia. Melatonin (30 mg/kg) was intraperitoneally administered in two doses: immediatelyfollowing HI, and 24 h later. Hypothermia consisted of whole-body cooling (3 hours,27℃). Sham-treated animals not subjected to HI were also studied. P10, P14, andP35 rats were sacrificed for experiments. Results: Vehicle-treated P10 rats increased in brain infarction compared to controlsin TTC staining study. And also, P35 rats decreased in brain volume of injured hemispherein H&E stain. Melatonin or hypothermia alone did not show any protectiveeffect against HI. However, a combination of melatonin and hypothermia effectivelyreduced the brain injury. In addition, the results of in situ zymography, TUNEL assayand immunofluorescence studies showed that neuroprotective effects were achievedonly with combined therapy. Conclusion: Melatonin may contribute to synergistic effects to neuroprotection ofhypothermia on brain damage after HI.

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