Background & Aims

Chronic pain, defined as pain which persists beyond 3 months, affects one in five people worldwide, and many of the treatments available are either ineffective or cause strong and serious side effects [1]. Nitenin, a marine natural molecule produced by marine sponges, is here described as highly effective at treating chronic pain [2]. By specifically acting upon voltage gated potassium channels expressed in peripheral pain-sensing neurons located outside of the spinal cord and brain [3] – the dorsal root ganglion (DRG) neurons -, nitenin appears to have no serious side effects, unlike current drugs on the market.

Methods

The potency of nitenin was screened against the voltage gated potassium channels expressed in the soma of small diameter DRG neurons, acutely isolated from rats subjected to neuropathic pain conditions. In vivo analgesic efficacy of nitenin was evaluated in Chronic Constriction Injury (CCI) neuropathic pain models. All procedures involving animal subjects (Rattus novergicus Wistar Han), were carried out at the rodent house of NOVA Medical School, in accordance with the institution’s Ethics Committee and the Directive 2010/63/UE. The statistical analysis was performed using a two-tailed unpaired student’s t test for samples size (n) ? 10 and the non-parametric Mann–Whitney U-test for n < 10, or for data that failed normality test.

Results

Whole cell potassium currents showed a significant current density reduction in the presence of nitenin, mainly over currents with slow kinetics of inactivation (IK): 365.4 ± 44.8 pA/pF and 251.1 ± 29.5 pA/pF, for control and ´treated’neurons, respectively, at 50mV; p = 0.042. Additionally, the neuronal firing frequency at the resting membrane potential (RMP) – ‘spontaneous activity’ – decreased upon the application of 2.9?M nitenin, indicating a pivotal role at cancelling the exacerbated activity of injured neurons: 5.65 ± 1.76 Hz and 0.30 ± 0.09 Hz, for control and ‘treated’ neurons, respectively; p = 0.0041. The analgesic efficacy of nitenin was demonstrated in CCI neuropathic pain models, as a low dose (0.6mpk) intravenously administered alleviated pain compared with vehicle controls. Nitenin-treated group depicted a significant higher maximum possible effect (%MPE), – 52.35 ± 9.81 % -, when compared to the vehicle group – 11.80 ± 3.67 % -; p= 1.96×10-6.

Conclusions

Altogether the results show nitenin is a molecule with analgesic properties that can be perceived as a novel therapeutic approach to treat chronic pain, through a mechanism of action different from the solutions already in the market, especially when compared to those that cause addiction and habituation.

References

[1]. Breivik, H.; Eisenberg, E.; O’Brien, T. BMC Public Health 2013, 13, doi:10.1186/1471-2458-13-1229.
[2]. Lima, P. et al. Nitenin Analogue Compounds and their use in the treatment of chronic and acute pain. 2020; WO/2021/019373.
[3]. Lima, P. et al. Kv1.3 Antagonists for use in the treatment of chronic and acute pain. 2020; WO2021/019375.

Presenting Author

André Bastos

Poster Authors

Andre Bastos

PhD

Sea4Us, SA

Lead Author

Beatriz Szwarc

MSc

Sea4Us, SA

Lead Author

Ana Rosa Abreu

MSc

Sea4Us, SA

Lead Author

Miguel Mondragão

Lead Author

Pedro Afonso Lima

PhD

Sea4Us, SA

Lead Author

Topics

  • Treatment/Management: Pharmacology: Non-opioid