Capsaicin is a natural compound found in chili peppers and is used in the diet of many countries. The important mechanism of action of capsaicin is its influence on TRPV1 channels in nociceptive sensory neurons. Furthermore, the beneficial effects of capsaicin in cardiovascular and oncological disorders have been described. Many recent publications show the positive effects of capsaicin in animal models of brain disorders. In Alzheimer’s disease, capsaicin reduces neurodegeneration and memory impairment. The beneficial effects of capsaicin in Parkinson’s disease and depression have also been described. It has been found that capsaicin reduces the area of infarction and improves neurological outcomes in animal models of stroke. However, both proepileptic and antiepileptic effects of capsaicin in animal models of epilepsy have been proposed. These contradictory results may be caused by the fact that capsaicin influences not only TRPV1 channels but also different molecular targets such as voltage-gated sodium channels. Human studies show that capsaicin may be helpful in treating stroke complications such as dysphagia. Additionally, this compound exerts pain-relieving effects in migraine and cluster headaches. The purpose of this review is to discuss the mechanisms of the beneficial effects of capsaicin in disorders of the central nervous system.

The medial prefrontal cortex (PFC) is involved in cognitive functions, which undergo profound changes during adolescence. This alteration of the PFC function derives from neuron activity, which, in turn, may depend on age-dependent properties and the expression of neuronal ion channels. BK-type channels are involved in controlling both the Ca++ ion concentration in the cell interior and cell excitability. The purpose of this study was to test the properties of BK currents in the medial PFC pyramidal neurons of young (18–22-day-old), adolescent (38–42-day-old) and adult (58–62-day-old) rats. Whole-cell currents evoked by depolarizing voltage steps were recorded from dispersed medial PFC pyramidal neurons. A selective BK channel blocker – paxilline (10 µM) – irreversibly decreased the non-inactivating K+ current in neurons that were isolated from the young and adult rats. This current was not significantly affected by paxilline in the neurons obtained from adolescent rats. The properties of single-channel K+ currents were recorded from the soma of dispersed medial PFC pyramidal neurons in the cell-attached configuration. Of the K+ channel currents that were recorded, ~90% were BK and leak channel currents. The BK-type channel currents were dependent on the Ca++ concentration and the voltage and were inhibited by paxilline. The biophysical properties of the BK channel currents did not differ among the pyramidal neurons isolated from young, adolescent and adult rats. Among all of the recorded K+ channel currents, 38.9%, 12.7% and 21.1% were BK-type channel currents in the neurons isolated from the young, adolescent and adult rats, respectively. Furthermore, application of paxilline effectively prolonged the half-width of the action potential in pyramidal neurons in slices isolated from young and adult rats but not in neurons isolated from adolescent rats. We conclude that the availability of BK channel currents decreases in medial PFC pyramidal neurons of adolescent rat

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED₅₀ MES = 49.6 mg/kg, ED₅₀ 6 Hz (32 mA) = 31.3 mg/kg, ED₅₀scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED₅₀ = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.