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The Upregulation of L1CAM by SVHRSP Mitigates Neuron Damage, Spontaneous Seizures, and Cognitive Dysfunction in a
Zhen Li1, Biying Ge1,2, Haoqi Li1
1National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian 116044, China.
Abstract:
Temporal lobe epilepsy (TLE) is a common drug-resistant form of epilepsy, often accompanied by cognitive and emotional disturbances, highlighting the urgent need for novel therapies. Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP), isolated and synthetically derived from scorpion venom, has shown anti-epileptic and neuroprotective potential. This study evaluated the anti-epileptic effects of SVHRSP in a kainic acid (KA)-induced TLE rat model. Our results demonstrated that SVHRSP (0.81 mg/kg/day) reduced the frequency and severity of spontaneous seizures. Behavioral tests showed improved cognitive performance in the novel object recognition, object location, and T-maze tasks, as well as reduced anxiety-like behavior in the open-field test. Moreover, SVHRSP mitigated hippocampal neuronal loss and glial activation. Transcriptomic analysis indicated that SVHRSP upregulates genes involved in adhesion molecule-triggered and axon guidance pathways. Western blotting and immunofluorescence further confirmed that SVHRSP restored dendritic (MAP2), axonal (NFL), and synaptic (PSD95) marker expression, elevated the functionally important L1CAM fragment (L1-70), and increased myelin basic protein-induced serine protease activity responsible for L1-70 generation. Blockade of L1CAM expression diminished the neuroprotective effects of SVHRSP, suggesting a critical role for L1CAM-mediated synapse functions. This study is the first to reveal the therapeutic potential of SVHRSP in TLE via L1CAM-associated mechanisms.
Insights
Scorpion venom peptide (SVHRSP) effectively treated drug-resistant temporal lobe epilepsy (TLE) in rats. It reduced seizures, improved cognition, and protected neurons by enhancing L1CAM-mediated synapse function.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Temporal lobe epilepsy (TLE) is a prevalent, drug-resistant epilepsy often linked to cognitive and emotional deficits.
- Existing therapies for TLE are limited, necessitating the development of novel therapeutic strategies.
- Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP) exhibits potential anti-epileptic and neuroprotective properties.
Purpose of the Study:
- To investigate the anti-epileptic and neuroprotective effects of SVHRSP in a kainic acid-induced TLE rat model.
- To elucidate the underlying molecular mechanisms, particularly the role of L1CAM, in SVHRSP's therapeutic action.
Main Methods:
- Induction of TLE in rats using kainic acid (KA).
- Administration of SVHRSP and assessment of seizure frequency and severity.
- Behavioral testing including novel object recognition, object location, T-maze, and open-field tests.
- Histological analysis of hippocampal tissue for neuronal loss and glial activation.
- Transcriptomic analysis to identify affected pathways.
- Western blotting and immunofluorescence to evaluate protein expression (MAP2, NFL, PSD95, L1CAM).
Main Results:
- SVHRSP treatment significantly reduced seizure frequency and severity in the TLE rat model.
- SVHRSP administration improved cognitive functions and reduced anxiety-like behaviors.
- Histological examination revealed mitigation of hippocampal neuronal loss and glial activation.
- Transcriptomic data indicated SVHRSP upregulates genes in adhesion molecule-triggered and axon guidance pathways.
- SVHRSP restored expression of dendritic, axonal, and synaptic markers and increased L1CAM fragment L1-70 levels.
- L1CAM blockade diminished SVHRSP's neuroprotective effects, highlighting L1CAM's crucial role.
Conclusions:
- SVHRSP demonstrates significant therapeutic potential for drug-resistant TLE.
- The anti-epileptic and neuroprotective effects of SVHRSP are mediated, at least in part, through L1CAM-associated synaptic mechanisms.
- This study provides novel insights into SVHRSP as a potential treatment for TLE, targeting L1CAM-mediated pathways.
