Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.706225
Keywords
cytisine; temporal lobe epilepsy; neuroprotection; synaptic remodeling; cholinergic transmission; alpha 7nAChRs
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Funding
- Natural Science Project of the Department of Education of Guangdong Province [2019KTSCX138]
- Key Project of Science and Technology Program of Guangzhou [201804020023]
- National Natural Science Foundation of China [81772699, 82073047]
- Science and Technology Programs of Guangdong Province [2017B030301009]
- Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties [SZGSP013]
- College Student's Science and Technology Innovation Project of Guangzhou Medical University [2019A031]
- College student's Innovation and Entrepreneurship Training Program of Guangdong Province [S202010570068, S202010570026]
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The study demonstrated that cytisine exerts an antiepileptic and neuroprotective effect in TLE rats through activation of α7nAChRs, leading to a decrease in glutamate levels, inhibition of synaptic remodeling, and improvement of cholinergic transmission in the hippocampus.
Background and Purpose: Temporal lobe epilepsy (TLE) is a common chronic neurological disease that is often invulnerable to anti-epileptic drugs. Increasing data have demonstrated that acetylcholine (ACh) and cholinergic neurotransmission are involved in the pathophysiology of epilepsy. Cytisine, a full agonist of alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs) and a partial agonist of alpha 4 beta 2nAChRs, has been widely applied for smoking cessation and has shown neuroprotection in neurological diseases. However, whether cytisine plays a role in treating TLE has not yet been determined. Experimental Approach: In this study, cytisine was injected intraperitoneally into pilocarpine-induced epileptic rats for three weeks. Alpha-bungarotoxin (alpha-bgt), a specific alpha 7nAChR antagonist, was used to evaluate the mechanism of action of cytisine. Rats were assayed for the occurrence of seizures and cognitive function by video surveillance and Morris water maze. Hippocampal injuries and synaptic structure were assessed by Nissl staining and Golgi staining. Furthermore, levels of glutamate,gamma-aminobutyric acid (GABA), ACh, and alpha 7nAChRs were measured. Results: Cytisine significantly reduced seizures and hippocampal damage while improving cognition and inhibiting synaptic remodeling in TLE rats. Additionally, cytisine decreased glutamate levels without altering GABA levels, and increased ACh levels and alpha 7nAChR expression in the hippocampi of TLE rats. alpha-bgt antagonized the above-mentioned effects of cytisine treatment. Conclusion and Implications: Taken together, these findings indicate that cytisine exerted an anti-epileptic and neuroprotective effect in TLE rats via activation of alpha 7nAChRs, which was associated with a decrease in glutamate levels, inhibition of synaptic remodeling, and improvement of cholinergic transmission in the hippocampus. Hence, our findings not only suggest that cytisine represents a promising anti-epileptic drug, but provides evidence of alpha 7nAChRs as a novel therapeutic target for TLE.
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