PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pharmaceutical Sciences I.

The Effects of Tolperisone on Neuronal Glutamate Release

Péter P. Lakatos1; Mahmoud Al-Khrasani2; Tamás Tábi1; Éva Szökő1
1Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
2Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary

Text of the abstract

Introduction: Tolperisone is a centrally acting muscle relaxant that also affects nociceptive neurotransmission. In our previous experiments hyperalgesia, a symptom of neuropathic pain was significantly alleviated by tolperisone. Although an inhibitory effect on both voltage-gated sodium and calcium channels has been suggested, its exact mechanism of action still remains elusive.
Aims: Our aim was to examine the possible inhibitory effect of tolperisone on the release of glutamate, a neurotransmitter that plays a major role in nociception.
Method: Glutamate content of cerebrospinal fluid of sciatic nerve ligated neuropathic rats was measured and compared to that of the tolperisone-treated and sham-operated animals. Rat brain synaptosomes were used to examine the effect of tolperisone on glutamate release. Glutamate levels were determined using a capillary electrophoresis laser induced fluorescence method developed in our laboratory.
Results: Sciatic nerve ligation caused a significant elevation in cerebrospinal fluid glutamate content compared to sham-operated animals. A single-dose of tolperisone normalized glutamate concentrations suggesting that it may inhibit neuronal glutamate release.
In order to understand its mechanism of action, the direct effect of tolperisone on glutamate release was examined using rat brain synaptosomes. Tolperisone caused a concentration-dependent inhibition of sodium channel-dependent glutamate release elicited by 4-aminopyridine, similarly to the established sodium channel inhibitors, tetradotoxin and lidocaine. The largely sodium channel-independent release induced by KCl was unaffected by tolperisone, while the N-type calcium channel inhibitor, ω-conotoxin MCVIIA was still effective.
Conclusion: We have demonstrated for the first time that tolperisone both normalizes the increased cerebrospinal fluid glutamate levels in neuropathic pain and inhibits glutamate release from brain synaptosomes. Furthermore, its mechanism of action is now better understood as our results strongly suggest the involvement of synaptic voltage-gated sodium channel inhibition in the analgesic effect of tolperisone.
Funding: The project was funded by Semmelweis University 250+ PhD Scholarship (EFOP-3.6.3-VEKOP-16-2017-00009)