Central Nervous System Safety Assessment

There are a variety of ion channels on the dorsal root ganglia, and sodium channels are associated with diseases such as pain. After nerve injury, the activity of voltage-gated sodium channels is altered, resulting in increased neuronal excitability and abnormal spontaneous discharge. Recent studies have shown that a variety of voltage-gated sodium channels are involved in nerve pain-related mechanisms, mainly Nav1.7 and Nav1.8 channels.

 

LeadQuest Biotech employs neuropharmacology, neuroscience, neuroimmunology, and neurophysiology to conduct Safety Assessments of the Central Nervous System.

 

Neuropharmacology

Neuropharmacology study how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior.

 

Stock Animal Models of Pain Include

• Chronic Constriction Injury of the Sciatic Nerve Model (CCI, Rat/Mouse)
• Sciatic Nerve Branch Selective Ligation Model (SNI, Rat/Mouse)
• Spinal Nerve Ligation Model (SNL, Rat/Mouse)
• Complete Freund’s Adjuvant (CFA)-Induced Inflammatory Pain Model
• Acetic Acid Writhing (Rat/Mouse)
• Visceral Pain Model (Rat)

 

1.Epilepsy Model

Epilepsy is a chronic brain dysfunction syndrome caused by highly synchronized abnormal discharges of groups of neurons in the brain due to various etiologies,which is characterized by recurrent, sudden and temporary. The location and spread of the abnormally discharging neurons lead to different seizure manifestations in patients. In severe cases, it may cause symptoms such as sudden loss of consciousness, generalized convulsions, and psychiatric abnormalities. These episodes can significantly harm the patient’s body and even be life-threatening. Frequent seizures can also cause substantial damage to the brain.

 

Epidemiological data indicates that there are over 9 million people with epilepsy in China, with approximately 650,000 to 700,000 new cases diagnosed each year. Among these, about 30% suffer from intractable epilepsy. Therefore, it is of profound significance to strengthen the prevention and research of epilepsy, to provide integrated services for early-stage antiepileptic compound screening for pharmaceutical companies developing antiepileptic drugs, and to further enhance the clinical translation rate of drug development targeting specific epilepsy-related biomarkers.

 

Targets of antiepileptic drugs can be divided into the following four categories:

 

1)Action on voltage-gated ion channels, including sodium, calcium, and potassium channels.

2)Enhancement of inhibitory effects mediated by GABA receptors.

3)Inhibition of excitatory effects mediated by glutamate receptors (NMDA, AMPA).

4)Direct regulation of synaptic release through components of release mechanisms (SV2A, voltage-gated channel α2δ subunit).

 

These mechanisms aim to regulate the balance between intrinsic excitability and inhibitory processes in neurons, reducing the likelihood of synchronized discharges in local neurons and thereby lowering the risk of epileptic seizures.

 

The heterogeneity and complexity of epileptic seizures, along with the variety of drugs patients may have previously used, result in relatively low success rates for single-target approaches and single-model strategies in the design and discovery of antiepileptic drugs. Therefore, in the development of antiepileptic drugs, it is crucial to employ multi-target designs and a variety of models for prediction and validation. Early comprehensive screening should integrate multiple different animal models to thoroughly evaluate the efficacy of potential therapeutic drugs. This approach allows for a more robust assessment of how a drug might perform in various seizure types and conditions, increasing the likelihood of identifying effective treatments for epilepsy.

 

In preclinical research, rodent epilepsy models are commonly used to evaluate the antiepileptic effects of compounds. The frequently used animal models include:The Maximal Electroshock (MES) Model,The Pentylenetetrazol (PTZ) Induced Epilepsy Model,The 6 Hz Psychomotor Seizure Model,The Amygdala Kindling Model.Each of these models presents different aspects of human epileptic seizures and is used to assess the potential effectiveness of antiepileptic compounds in a variety of seizure types, as illustrated in Table 1.

 

Table 1. Epilepsy Animal Model of Rodents and Its Antiepileptic Drug Mechanism

 

LeadQuest Biotech has established a comprehensive and integrated service platform that encompasses target selection/validation/screening, in vitro model testing, and in vivo model evaluation (including animal behavior and electroencephalography synchronization monitoring), providing high-quality antiepileptic drug screening and pharmacodynamic evaluation services for pharmaceutical research and development companies.

 

Table 2. Research and Development of Antiepileptic Drugs

 

LeadQuest Biotech possesses high-expression ion channel cells for antiepileptic drug target selection/validation/screening as follows:

 

Table 3. High-Expression Ion Channel Cells for Antiepileptic Drug Target Selection/Validation/Screening

 

2.Cerebral Ischemia Model

• Brain Ischemia Model
• Oxygen-Glucose Deprivation (OGD) Model
• Chemical Injury Model
• Animal Focal Cerebral Ischemia Model (MCAO)
• Global Cerebral Ischemia Model

 

1)Brain Ischemia Model

Currently, we use the filament method for modeling in both mice (C57♂26-30g) and rats (SD♂240-270g). The filament is inserted from the external carotid artery into the common carotid artery, then into the internal carotid artery, and finally reaches intracranially. The occlusion lasts for 60-120 minutes, followed by reperfusion for 24 hours.

2)Middle Cerebral Artery Occlusion(MCAO)Experiment in Rats

3)Middle Cerebral Artery Occlusion(MCAO)Experiment in Mice

 

3.Neurodegenerative Diseases Model

Alzheimer’s Disease – 5×FAD model

 

Neuroelectrophysiology

Neuroelectrophysiology study the electrical properties and activities of neurons and neural networks, typically using techniques such as electrophysiological recordings, voltage and current clamping, and patch clamping. It aims to understand the function and dysfunction of the nervous system at the cellular and network levels.

 

The Dorsal Root Ganglion (DRG) functions as an essential neuronal element within the sensory conduction pathway, executing a dual function in both transmitting and modulating sensory experiences, especially in terms of receiving and relaying nociceptive signals. DRG as a critical model for exploring neuropathic pain treatments, gaining significant research interest in areas such as pain mechanism elucidation and therapeutic development. Particularly noteworthy in this regard are the ion channels and their receptors, which are intimately linked to pain perception, which are crucial for targeted pain mitigation in the DRG.

 

Within the DRG, an array of ion channels is present, with sodium channels being intimately associated with pain and various neurological disorders. Following neural injury, changes in the activity of voltage-gated sodium channels result in heightened neuronal excitability and the emergence of abnormal spontaneous discharges. Cutting-edge research has revealed that several voltage-gated sodium channels, most notably Nav1.7 and Nav1.8, play key roles in the mechanisms underlying neuropathic pain.

 

The Nav1.8 channel, which is Tetrodotoxin (TTX)-resistant, represents a sodium channel that is predominantly expressed in the DRG’s small-diameter C-fiber neurons. It plays a central role in the development of peripheral sensitization associated with inflammatory and neuropathic pain. Animal studies have shown that in rat models of inflammatory and neuropathic pain, there is a significant increase in the expression of Nav1.8 channels, underscoring their importance in pain research.

 

Other Neuroelectrophysiology Solutions:

• Proteomics
• Membrane Protein Expression
• Bioinformation Analysis
• Cryo-EM Platform
• Virtual Screening
• Small Molecule High-throughput Screening