Advances in Neurotoxicity Screening

Neurotoxicity screening is the procedure of using an in vitro or in vivo model to evaluate the potential toxic effects of a drug on the nervous system in order to identify drugs that may manifest neurotoxicity. This is done in order to screen and identify drugs that have the potential to cause harm to the nervous system during the early stages of drug development, thereby avoiding clinical trial failure. Table 1 compares different neurotoxicity screening methods.

Table 1 Comparison of neurotoxicity screening methods.

Creative Biolabs has answered this need by offering advanced neurotoxicity drug screening services. With the help of Creative Biolabs, pharmaceutical companies can more effectively reduce potential safety issues, streamline drug development timelines, and improve the probability of clinical success.

Significance of Neurotoxicity Screening

Neurotoxicity screening plays a very important role in drug development and neurodegenerative disease research.

• Screen for drug candidates as early as possible to avoid clinical failure
• Save R&D cost and time, and reduce animal testing
• Help optimize drug design and reduce toxicity
• Help assess neurodegenerative diseases and develop treatment methods

Methods of Neurotoxicity Screening

Neurotoxicity screening is an important phase of the drug safety evaluation process. Traditional neurotoxicity screening methods include animal models and immortalized cell lines, but these methods have some significant problems, including notable interspecies variations, ethical issues, low throughput, and a lack of human relevance. The advent of stem cell technologies has created in vitro models more physiologically similar to humans that have reached an equilibrium between ethical value and scientific benefit.

Traditional Neurotoxicity Screening Methods

Traditional neurotoxicity screening primarily involves the following methods.

• First, animal models are used to assess neural functional damage through behavioral tests (e.g., motor coordination), histopathological sections, and electrophysiological recordings.
• Second, immortalized cell lines are employed, which are easy to handle but lack complex neural network functions.
• Third, primary neuronal cultures are conducted, which retain some physiological characteristics but are limited in source and exhibit significant batch-to-batch variability.

The core deficiencies of traditional neurotoxicity screening methods are evident.

• On one hand, there are species differences issues, as animal models cannot accurately simulate human neurodegenerative diseases (such as Alzheimer's disease), leading to a clinical trial failure rate as high as 99.6%.
• On the other hand, there is a low-throughput issue, as animal experiments have long cycles (months) and high costs, making it difficult to meet the demands of large-scale drug screening.
• Additionally, there are functional assessment limitations, as real-time monitoring of neural network dynamic activity is not possible.

Stem Cell Neurotoxicity Screening

The advantages of using pluripotent stem cells (hPSCs) and induced pluripotent stem cells (iPSCs) in neurotoxicity testing include:

• High physiological relevance
  hPSCs/iPSCs can be differentiated into functional human neural networks (neurons/glial cells, etc.) with structural and functional fidelity to the human nervous system, greatly reducing animal testing and species differences bias.
• Ethical and practical advantages
  iPSCs bypass the ethical concerns of embryonic stem cell applications, and the use of autologous cells minimizes immune rejection, laying the foundation for personalized toxicity testing.
• High-efficiency technology integration potential
  Enables high-throughput screening (such as microelectrode array detection of neural activity) and multi-parameter evaluation (gene expression/epigenetic analysis). Integrated with 3D culture technology, it can be upscaled to complex models, significantly improving testing efficiency and mechanism research depth.

Breakthroughs in Neurotoxicity Screening Technology

3D Neural Spheroids

3D neural spheroids are formed by neural stem cells (e.g. neurons from iPSCs) in scaffold-free or hydrogel materials. These models can simulate three-dimensional neuronal connection and network formation. It has the advantages of retaining pluripotency of neurons, and being able to differentiate into neurons, astrocytes and other cells in 3D, and the resulting in vivo neurotoxicity response is closer.

The combination of 3D neural spheroids with high-throughput screening technology and high-content imaging can rapidly evaluate compounds. For example, the pattern and frequency of calcium oscillation can be used to quantify neurotoxicity effects. Moreover, 3D microarray platforms can also be used to carry out high-throughput screening to evaluate the toxicity of small molecules to neural stem cells.

Organoid Models

3D organoids established from hESCs/iPSCs can recapitulate the complex structure and function of the human brain, and provide neurotoxicity data more relevant to the in vivo state.

• Midbrain, hippocampus, and cerebellum organoids have been used to assess drug-induced neurotoxicity.
• By combining 3D organoids with microfluidic chips and other bioengineering techniques (e.g. 3D-printed vascular networks), the organoid function can be further optimized.

Figure 1 Organoids have a high degree of histological and functional similarity with the human brain^1,2

Organ-on-a-chip

Organ-on-a-chip systems connect multiple organ units by microfluidic channels to simulate organ-organ interactions. For example, the process of drug absorption in an intestinal chip, metabolism in a liver chip, and excretion in a kidney chip can simulate the entire pharmacokinetic process. This method can be used for drug screening and toxicity evaluation, and can reduce the use of animal experiments.

Emerging neurotoxicity screening platforms are transforming the landscape of potential neurotoxic effect assessment. These innovative approaches offer higher physiological relevance, enhanced throughput, and ethical advantages, enabling a more accurate prediction of drug safety and streamlining the drug development process.

At Creative Biolabs, we are dedicated to offering tailored, comprehensive neurotoxicity screening services to address the evolving demands of drug research and development. Contact us today to discover how our cutting-edge technology and expert team can support your project and contribute to the development of safer, more effective therapeutic treatments.

References

1. Park, Si-Hyung, and Woong Sun. "Toxicity Assessment Using Neural Organoids: Innovative Approaches and Challenges." Toxicological Research, vol. 41, no. 2, Mar. 2025, pp. 91–103. DOI.org, https://doi.org/10.1007/s43188-025-00279-y.
2. Distributed under Open Access license CC BY 4.0, without modification.

Created June 2025

For Research Use Only. Not For Clinical Use.