Cerebellar injury due to phenytoin. Identification and evolution of Purkinje cell axonal swellings in deep cerebellar nuclei of mice

Kiefer, R.; Knoth, Rolf; Anagnostopoulos, J.; Volk, Benedikt

doi:10.1007/bf00687581

Cited by 24 publications

(4 citation statements)

References 45 publications

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“…The pons relays information from cerebral cortex to the cerebellum and is a region of high metabolic exchange. Handed penetration of drugs such as phenytoin and ethanol along this barrier exerts neurotoxic effects especially in cerebellum [75][76][77]. The expression profile of P450s at the CSF-brain barrier supports our hypothesis.…”

Section: Cerebrospinal Fluid (Csf) -Brain Barriersupporting

confidence: 83%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

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130

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Cytochrome P450 (CYP, P450) is the collective term for a superfamily of heme-containing membrane proteins responsible for the metabolism of approximately 70 - 80 % of clinically used drugs. Besides the liver and other peripheral organs, P450 isoforms are expressed in glial cells and neurons of the brain. To enlighten their function and significance is a topic of high interest, as most of the neuroactive drugs used in therapy today are not only substrates, but also inducers of brain P450s with far reaching consequences. First of all, brain P450s are regulated differentially from those in liver. The availability of the prosthetic heme group appears to be essential for correct membrane insertion and enzymatic functionality of brain P450s. Furthermore, although not contributing to body's overall drug metabolism, brain P450s fulfil particular functions within specific cell types of the brain. In astrocytes of brain's border lines P450 isoforms are expressed at very high level. They form a metabolic barrier regulating drugs' influx, modulate blood-flow regulation, and act as signalling enzymes in inflammation. In neurons, however, P450s apparently have different function. In specified brain regions such as hypothalamus, hippocampus and striatum they provide signalling molecules like steroids and fatty acids necessary for neuronal outgrowth and maintenance. Induction of these P450s by neuroactive drugs can alter steroid hormone signalling directly in drug target cells, which may cause clinically relevant side effects like reproductive disorders and sexual or mental dysfunction. The understanding of brain P450 function appears to be of major interest in long-term drug mediated therapy of neurological diseases.

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Section: Cerebrospinal Fluid (Csf) -Brain Barriersupporting

confidence: 83%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

Self Cite

130

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“…Basically, such effects on neurons have been repeatedly investigated, e.g., for Purkinje cells (Jones and Wimbish, 1985;Volk and Kirchgässner, 1985;Kiefer et al, 1989). Enforced attempts to analyze cytochromes P450 directly in astrocytes might be helpful to understand the scattered action of phenytoin in the context of epilepsy therapy.…”

Section: Effects Of Phenytoin On Cyp2b Mrnas As Determined By Rt/pcrmentioning

confidence: 98%

Effect of phenytoin on cytochrome P450 2B mRNA expression in primary rat astrocyte cultures

et al. 1998

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Studies on cytochrome P450 2B (CYP2B) in the brain have essentially been focused on protein characterization and regional distribution. Due to the high sequence homology between the closely related CYP2B1 and 2B2 isoforms and the low amounts of the corresponding mRNAs few efforts have been made to analyze the expression, regulation, and inducibility of these P450 genes in a specific cell type. In the present study, we investigated CYP2B mRNA expression in primary rat astrocyte cultures under the influence of the anti-epileptic drug phenytoin, which is known to be a CYP2B inducing agent in liver. In situ hybridization with a digoxigenin (DIG)-labeled cRNA probe demonstrated that 30-40% of the astrocytes strongly expressed a CYP2B mRNA-specific signal within the first week of cultivation. With increasing age (> 14 days) a greater percentage of cells (>90%) expressed mRNA for P450 2B. However, the level of transcriptional activity was substantially lower than in younger cultures. To discriminate between the 2B1 and 2B2 isoforms the reverse transcription/polymerase chain reaction (RT/PCR) procedures were proved for rat hepatic mRNA as a control assay. Subsequently, the application of this method on cultured astrocytes confirmed that these brain cells may express CYP2B1 mRNA. CYP2B2 mRNA could not be detected in astrocyte cultures at any age examined. Phenytoin led to the down regulation of CYP2B1 mRNA, which contrasts with the drug inducing effect on hepatic CYP2B1 and 2B2 levels. After 4 hr of exposure of phenytoin to the astrocytes no amplification product could be detected at all. Phenytoin did not induce either CYP2B1 or 2B2 expression.

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“…O estabelecimento de correlação inequívoca entre o uso de fenitoína e a atrofia cerebelar é difícil pois, na maioria dos casos, além do uso da medicação anticonvulsivante, os pacientes também apresentam crises tônico-clônicas generalizadas e hipóxia decorrente destas crises. Alterações cerebelares caracterizadas por lesão das células de Purkinje foram demonstradas experimentalmente em animais com níveis séricos de fenitoína elevados 14,15 . Rapport & Shaw 4 estabeleceram com maior segurança a relação entre fenitoína e atrofia cerebelar ao relatar este achado em um paciente tratado profilaticamente com fenitoína e que nunca havia apresentado crise epiléptica.…”

Section: Discussionunclassified

Relação dose-dependente do uso crônico de fenitoína e atrofia cerebelar em pacientes com epilepsia

Negro¹,

Dantas²,

Zanardi

et al. 2000

Arq. Neuro-Psiquiatr.

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RESUMO -O uso crônico da fenitoína ou intoxicação aguda por essa droga produzem lesão cerebelar permanente com atrofia do vermis e hemisférios cerebelares, que pode ser evidenciada através de exames de neuroimagem. O objetivo deste estudo foi avaliar a correlação entre a dosagem e o tempo de uso da fenitoína com a ocorrência de atrofia cerebelar. Foram realizados levantamento de prontuários para a obtenção de dados clínicos e análise de tomografias de crânio para avaliação de atrofia cerebelar. Dos 66 pacientes estudados, 18 apresentaram atrofia moderada a severa, 15 atrofia leve e 33 foram considerados normais. Os pacientes com atrofia cerebelar moderada a severa foram aqueles com maior exposição à fenitoína (uso prolongado e dose total), apresentando diferença estatisticamente significativa se comparados aos pacientes com atrofia leve ou sem atrofia (p=0.02). Além disso, no subgrupo de pacientes em uso de fenitoína, aqueles com atrofia moderada a severa possuíam níveis séricos de fenitoína significativamente mais elevados que os pacientes com atrofia leve ou sem atrofia (p=0.008). Não houve relação entre duração do tratamento e dose de outros anticonvulsivantes e presença e grau de atrofia cerebelar. Os pacientes mais velhos apresentaram maior grau de atrofia cerebelar, indicando que o fator idade ou tempo de epilepsia, ou ambos, pode ser importante na determinação de degeneração cerebelar. Concluímos que apesar da possibilidade de lesão cerebelar relacionada a crises epilépticas repetidas, a contribuição da fenitoína pode ser claramente estabelecida como um dos determinantes da atrofia cerebelar, sobretudo naqueles pacientes com altas doses por tempo prolongado e níveis séricos elevados. PALAVRAS-CHAVE: fenitoína, atrofia cerebelar, epilepsia. Dose-related cerebellar atrophy in patients with epilepsy using phenytoinABSTRACT -The chronic treatment with phenytoin or the acute intoxication by this drug may cause permanent cerebellar injury with atrophy of cerebellum vermis and hemispheres, which can be detected by neuroimaging studies. The aim of the present study was to investigate the correlation between the dosage and duration of treatment with phenytoin and the occurrence of cerebellar atrophy. Sixty-six patients were studied and had their tomographies analyzed for cerebellar atrophy. Of the 66 patients studied, 18 had moderate/severe atrophy, 15 had mild atrophy and 33 were considered to be normal. The patients with moderate/severe atrophy were those with higher exposure to phenytoin (longer duration of treatment and higher total dosage) showing statistically significant difference when compared to patients with mild atrophy or without atrophy (p=0.02). Further, the patients with moderate/severe atrophy had serum levels of phenytoin statistically higher than those of patients with mild atrophy or without atrophy (p = 0.008). There was no association between other antiepileptic drugs dosage or duration of treatment and degree of cerebellar atrophy. We also found that older patients had cerebellar atrophy mor...

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Cerebellar injury due to phenytoin. Identification and evolution of Purkinje cell axonal swellings in deep cerebellar nuclei of mice

Cited by 24 publications

References 45 publications

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Effect of phenytoin on cytochrome P450 2B mRNA expression in primary rat astrocyte cultures

Relação dose-dependente do uso crônico de fenitoína e atrofia cerebelar em pacientes com epilepsia

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