Dataset Information

Effects of carbamazepine on the central nervous system of zebrafish at human therapeutic plasma levels.

ABSTRACT: The fish plasma model (FPM) facilitated the environmental risk assessment of human drugs by using existing data on human therapeutic plasma concentrations (H_TPCs) and predicted fish plasma concentrations (FPCs). However, studies on carbamazepine (CMZ) with both the mode of action (MOA) based biological effects at molecular level (such as neurotransmitter and gene level) and measured FPCs are lacking. Bioconcentration of CMZ in adult zebrafish demonstrated that the FPM underestimated the bioconcentration factors (BCFs) in plasma at environmental CMZ exposure concentrations (1-100 μg/L). CMZ significantly increased Glu and GABA, decreased ACh and AChE as well as inhibited the transcription levels of gabra1, grin1b, grin2b, gad1b, and abat when the actual FPCs were in the ranges of 1/1000 H_TPC to H_TPC. It is the first read-across study of CMZ integrating MOA-based biological effects at molecular level and FPCs. This study facilitates model performance against a range of different drug classes.

SUBMITTER: Yang W

PROVIDER: S-EPMC10494213 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Effects of carbamazepine on the central nervous system of zebrafish at human therapeutic plasma levels.

Yang Weiwei W Bao Yifan Y Hao Jiaoyang J Hu Xialin X Xu Ting T Yin Daqiang D

iScience 20230823 10

The fish plasma model (FPM) facilitated the environmental risk assessment of human drugs by using existing data on human therapeutic plasma concentrations (H<sub>T</sub>PCs) and predicted fish plasma concentrations (FPCs). However, studies on carbamazepine (CMZ) with both the mode of action (MOA) based biological effects at molecular level (such as neurotransmitter and gene level) and measured FPCs are lacking. Bioconcentration of CMZ in adult zebrafish demonstrated that the FPM underestimated t ...[more]

PMID: 37701572

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Project description:The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized "Trojan horse" techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.

Dataset Information

Effects of carbamazepine on the central nervous system of zebrafish at human therapeutic plasma levels.

Publications

Effects of carbamazepine on the central nervous system of zebrafish at human therapeutic plasma levels.

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