As the name indicates, neurotoxicity is the ability of a neurotoxin to induce adverse effects on the nervous system, including the central nervous system (CNS), peripheral nerves and sensory organs. Neurotoxins cause damage to the nervous tissue and alter the chemistry, structure or normal activity of the nervous system. Eventually the key cells that process and transmit signals in the nervous system, neurons, are disrupted or even killed, and a consistent pattern of neural dysfunction appears. Also, in utero exposure to neurotoxins can lead to altered development of the nervous system [developmental neurotoxicity (DNT)]. Symptoms of neurotoxicity include but not limit to headache, delusion, loss of memory and/or vision, limb weakness or numbness, and cognitive and behavioral problem. These symptoms may appear immediately after neurotoxin exposure or be delayed. Patients with certain disorders may be especially susceptible to neurotoxins. It is important to evaluate the neurotoxicity of drug candidates before applying them in human tests. Creative Biolabs provides superior platforms and approaches for neurotoxicity evaluation for drug candidates.
Like other toxicity studies, neurotoxicity tests for regulatory purposes normally involve in vivo animal tests.
Delayed Neurotoxicity Study Following Acute Exposure
A single oral dose of the testing compound is administrated to hens. Then the hens are observed for 21 days for their weight, gross, behavior, and microscopic pathology.
Delayed Neurotoxicity Study
Delayed neurotoxicity study is similar to delayed neurotoxicity following acute exposure study, but with longer observation period.
Repeated Dose Study
This method involves repeated daily dosing of hens with the testing compound for 28 days. After that, biochemical and histopathological tests are performed.
Neurotoxicity Study in Rodents
Acute, subchronic, or chronic neurotoxicity evaluations (28 days/90 days/one year or longer) with daily oral dosing of rats are performed. Behaviors are observed and histopathology of the nervous system is evaluated.
Developmental Neurotoxicity (DNT) Study
At least 60 pregnant rats are supplied with the testing compound from implantation through lactation during pregnancy. In utero and early postnatal effects are observed. Neurologic and behavioral disorders, brain weight, and neuropathology of the offspring are evaluated.
| Level | Grouping | Explanation/Examples |
|---|---|---|
| 6 | Morphological changes | Morphological changes include cell death and axonopathy as well as subcellular morphological changes. |
| 5 | Neurological changes | Neurological change embraces abnormal findings in neurological examinations on single individuals. |
| 4 | Physiological/behavioral changes | Physiological/behavioral changes comprise experimental findings on groups of animals or humans such as changes in evoked potentials and EEG, or changes in psychological and behavioral tests. |
| 3 | Biochemical changes | Biochemical changes cover changes in relevant biochemical parameters (e.g., transmitter level, GFA-protein content (glial fibrillary acidic protein) or enzyme activities). |
| 2 | Irreversible, subjective symptoms | Subjective symptoms. No evidence of abnormality on neurological, psychological or other medical examination. |
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1
|
Reversible, subjective symptoms | Subjective symptoms. No evidence of abnormality on neurological, psychological, or other medical examination. |
Table 1. Relative strength for establishing neurotoxicity (Encyclopaedia of Occupational Health and Safety, 4th Ed, International Labour Office). 1 & 2 are human only.
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