Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice

Namgue Hong,Yun-Sik Choi,Seong Yun Kim,Hee Jung Kim 대한생리학회-대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.1

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium’s actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice

홍남규,최윤식,김성윤,김희정 대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.1

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium’s actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

간질 중첩증 환아에 대한 임상적 고찰

이승현,노영일,양은석,문경래,박영봉,박상기 조선의대 1998 The Medical Journal of Chosun University Vol.23 No.1

Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice

Hong, Namgue,Choi, Yun-Sik,Kim, Seong Yun,Kim, Hee Jung The Korean Society of Pharmacology 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.1

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

간질 중첩증 환자에서 산-염기 평형 장애에 관한 연구

신송희(Song Heui Shin),문경래(Kyung Rye Moon),노영일(Young Il Rho) 대한소아신경학회 2001 대한소아신경학회지 Vol.9 No.2

목 적: 경련성 간질 중첩증은 산-염기 평형장애를 초래한다. 일반적으로 과도한 근육 수축으로 인해 당원이 고갈되고 젖산 형성이 촉진되어 대사성 산증이 주로 발생한다고 알려져 있다. 그러나 최근에는 경련하는 동안 말초 호흡근과 신경이 피로하게 되면서 횡격막 운동이나 중추 호흡신경에 영향을 주어 호흡성 산증의 빈도가 높다는 보고가 있다. 저자들은 간질 중첩증 환자에서 산-염기 평형 장애를 알아보고 영향을 미칠 수 있는 인자에 대하여 조사하였다. 방 법: 1995년 1월부터 2000년 8월까지 5년 동안 조선대학교병원 소아과에 간질중첩증으로 입원 치료 하였던 25명의 환아를 대상으로 하여 후향적으로 조사하였다. 항경련제 투여전에 혈액가스 검사와 입원 후 첫 2일 동안 흉부 방사선 촬영을 하여 산-염기 평형장애와 폐침윤 여부, 경련의 형태 및 지속시간과의 관계를 알아보았다. 결 과: 1) 전체 25례 중 남아가 16례(64%), 여아가 9례(36%)로 남아가 많았고 평균연령은 2.4세(1개월-12세)였다. 2) 산-염기 평형장애는 25례 중 17례(68%)에서 있었으며, 호흡성 산증이 10례(40%)로 가장 많았고, 대사성 산증을 동반한 호흡성 산증 3례, 대사성 산증 3례, 호흡성 알칼리증 1례였고, 나머지 8례는 정산 산-염기 평형을 보였다. 3) 폐침윤은 전체 25례 중 8례(32%)에서 동반 되었으며, 이중 호흡성 산증 2례, 대사성 산증을 동반한 호흡성 산증 1례, 대사성 산증 3례, 정상 2례로 폐침윤과 산염기 평형 장애와는 상관관계가 없었다. 4) 경련의 형태는 25례 중 전신 강직 간대 발작이 18례(72%)로 가장 많았으며, 이들 중 9례가 호흡성 산증이었고, 대사성 산증과 동반된 호흡성 산증 2례로 호흡성 산증(61%)의 빈도가 높았다. 5) 경련의 지속시간에 따른 평균 pH는 30분-1시간에서 7.32±0.93, 1-3시간에서 7.23±0.17, 3시간이상에서 7.17±0.25로 경련의 지속시간이 길수록 pH는 의의있게 낮았다(P<0.05). 결 론: 간질 중첩증 환자에서는 대사성 산증보다 호흡성 산증이 발생하는 경우가 많았다. 폐침윤과 산염기 평형 장애와는 상관 관계가 없었으며 전신강직간대 발작의 경우 호흡성 산증의 빈도가 높았고 경련의 지속시간이 길수록 pH는 의의있게 낮았다. 경련이 멈춘 후 대부분 산염기 평형 장애에 대한 특별한 처치 없이도 정상 산-염기 평형을 보였으나, 사망한 2명의 경우에는 심한 대사성 산증과 함께 호흡성 산증이 동반되어 있었다. 그러나 호흡성 산증의 유무나 정도로 사망에 대한 예후를 예측하기는 어려울 것으로 생각된다. Purpose : Convulsive status epilepticus induces disturbance in acid-base homeostasis. It is known that metabolic acidosis is common after status epilepticus. A recent, discovery indicates respiratory acidosis is common after status epilepticus. This study is to analyze the acid-base disturbances in patients with status epilepticus. Methods : Retrospectively, we reviewed twenty-five patients with status epilepticus, who were admitted to the pediatric department of Chosun University Hospital between January 1995 and August 2000. We have analyzed the clinical correlation among the acid base disturbance, the incidence of pulmonary infiltration, and the type and duration of convulsions. Results : Acid-base disorders in the status epilepticus were revealed in 17(68%) of 25 patients. Respiratory acidosis with or without metabolic acidosis was most common(N= 13; 52%). There was no significant correlation between the pulmonary infiltration(N=8; 32%) and the acid-base disorders(P>0.05). The most common seizure type in status epilepticus was generalized tonic clonic(72%). In that type, the most common acid-base disorder was respiratory acidosis(11/18). The mean serum pH was significantly decreased with duration of seizures(P<0.05). Conclusion : This study finds that respiratory acidosis with or without metabolic acidosis was most common in status epilepticus. There was no significant correlation between pulmonary infiltration and acid-base disorders. Respiratory acidosis was most common in generalized tonic clonic seizure.

Lithium-Pilocarpine으로 중첩경련을 유발한 흰쥐에서 칼슘 통로 길항제가 해마에 미치는 영향

한시령,김영인,김범생 대한신경과학회 1997 대한신경과학회지 Vol.15 No.6

Differential Expression of Activating Transcription Factor-2 and c-Jun in the Immature and Adult Rat Hippocampus Following Lithium-Pilocarpine Induced Status Epilepticus

한시령,Cheolsu Shin,Seongkyung Park,Seonyoung Rhyu,Jeongwook Park,김영인 연세대학교의과대학 2009 Yonsei medical journal Vol.50 No.2

Purpose: Lithium-pilocarpine induced status epilepticus (LPSE) causes selective and age-dependent neuronal death, although the mechanism of maturation-related injury has not yet been clarified. The activating transcription factor-2 (ATF-2) protein is essential for the normal development of mammalian brain and is activated by c-Jun N-terminal kinase (JNK). It induces the expression of the c-jun gene and modulates the function of the c-Jun protein, a mediator of neuronal death and survival. Therefore, we investigated the expression of c-Jun and ATF-2 protein in the immature and adult rat hippocampus to understand their roles in LPSE-induced neuronal death. Materials and Methods: Lithium chloride was administrated to P10 and adult rats followed by pilocarpine. Neuronal injury was assessed by silver and cresyl violet staining, performed 72 hours after status epilepticus. For evaluation of the expression of ATF-2 and c-Jun by immunohistochemical method and Western blot, animals were sacrificed at 0, 4, 24, and 72 hours after the initiation of seizure. Results: Neuronal injury and expression of c-Jun were maturation-dependently increased by LPSE, whereas ATF-2 immunoreactivity decreased in the mature brain. Since both c-Jun and ATF-2 are activated by JNK, and targets and competitors in the same signal transduction cascade, we could speculate that ATF-2 may compete with c-Jun for JNK phosphorylation. Conclusion: The results suggested a neuroprotective role of ATF-2 in this maturation-related evolution of neuronal cell death from status epilepticus. Purpose: Lithium-pilocarpine induced status epilepticus (LPSE) causes selective and age-dependent neuronal death, although the mechanism of maturation-related injury has not yet been clarified. The activating transcription factor-2 (ATF-2) protein is essential for the normal development of mammalian brain and is activated by c-Jun N-terminal kinase (JNK). It induces the expression of the c-jun gene and modulates the function of the c-Jun protein, a mediator of neuronal death and survival. Therefore, we investigated the expression of c-Jun and ATF-2 protein in the immature and adult rat hippocampus to understand their roles in LPSE-induced neuronal death. Materials and Methods: Lithium chloride was administrated to P10 and adult rats followed by pilocarpine. Neuronal injury was assessed by silver and cresyl violet staining, performed 72 hours after status epilepticus. For evaluation of the expression of ATF-2 and c-Jun by immunohistochemical method and Western blot, animals were sacrificed at 0, 4, 24, and 72 hours after the initiation of seizure. Results: Neuronal injury and expression of c-Jun were maturation-dependently increased by LPSE, whereas ATF-2 immunoreactivity decreased in the mature brain. Since both c-Jun and ATF-2 are activated by JNK, and targets and competitors in the same signal transduction cascade, we could speculate that ATF-2 may compete with c-Jun for JNK phosphorylation. Conclusion: The results suggested a neuroprotective role of ATF-2 in this maturation-related evolution of neuronal cell death from status epilepticus.

집중치료실에서 치료한 중첩성 경련 환자의 신경생리학적 결과 분석

김대식 ( Dae Sik Kim ),김천식 ( Cheon Sik Kim ) 대한임상검사과학회 2005 대한임상검사과학회지(KJCLS) Vol.37 No.2

Status epilepticus is a medical emergency, so that rapid and vigorous treatment is required to prevent neuronal damage and systemic complication. Status epilepticus is generally defined as a continuous or intermittent seizure or an unconscious condition after the onset of seizure, lasting for 30 minutes or more. We report here the outcome of status epilepticus. We retrospectively reviewed medical record of 15 patients who were diagnosed with status epilepticus at the Asan Medical Center from January 2003 to February 2004. This outcome was evaluated considering various factors such as age of patients, history of seizures, neurologic impairment, etiology, mortality, return to baseline and initial electroencephalogram (EEG) findings. The range of age was between 1 to 79 years old and the longest duration of treatment was 118 days. Most patients were treated by using pentobarbital, midazolam, phenobarbital and other antiepileptic drugs. The overall mortality was 5 (33%) out of 15 patients. The mortality was related to etiology, underlying other medical conditions and initial EEG findings. 5 (55%) out of the 9 patients with acute etiology, 5 (71%) out of the 7 patients with a multifocal or burst-suppression EEG activity, and 3 (60%) out of the 5 patients with other medical disease were related to mortality. This data demonstrate high mortality due to status epilepticus. Mortality is related to etiology, other medical conditions and abnormalities on the initial EEG.

복합 부분 발작 중첩증 1례

한승규(Seung-Kyoo Han),전평(Pyoung Jeon) 대한소아신경학회 1999 대한소아신경학회지 Vol.7 No.1

본 저자는 출생 후 정상 발달을 보였고 경련의 과거력이 없었던 3세 환아에서, 임상적으로 약 24시간 동안 의식의 혼탁을 보여 시행한 뇌파 소견상 국소적인 극서파가 지속적으로 관찰되어 복합부분 발작 중첩증으로 진단한 증례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다. Nonconvulsive status epilepticus, which constitutes about 25% of all cases of status, has been subdivided into generalized nonconvulsine(absence) status and complex partial status. We report a case of complex partial status epilepticus in a 3-year-old male patient with altered mental function lasting about 24 hours. The electroencephalographic finding was compatible with complex partial status and the outcome of treatment is excellent, so far.

Pseudo Continuous Arterial Spin Labeling MR Imaging of Status Epilepticus

이민경,최승홍,정근화,윤태진,김지훈,손철호,장기현 대한자기공명의과학회 2012 Investigative Magnetic Resonance Imaging Vol.16 No.2

Purpose : The purpose of this study was to describe arterial spin labeling MR image findings of status epilepticus. Materials and Methods: A retrospective chart review within our institute revealed six patients who had been clinically diagnosed as status epilepticus and had also undergone MR imaging that included ASL in addition to routine sequences. Results: Six patients with status epilepticus were studied by conventional MR and arterial spin labeling imaging. All patients showed increased regional CBF correlating with EEG pathology. Notably, in two patients, conventional MRI and DWI showed no abnormal findings whereas pCASL demonstrated regional increased CBF in both patients. Conclusion: Arterial spin labeling might offer additional diagnostic capabilities in the evaluation of patients with status epilepticus.