Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury

Abstract

Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury.

Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis

“…These toxicokinetic factors could contribute to the preferential sensory toxicity of CTXs. Consistent with this, peripheral nerves were the main tissues in which P-CTX-1 was quantified 2 h after intraperitoneal exposure, ahead of the intestine, kidneys, stomach, liver, heart and muscles [ 209 ].…”

Biomaterials and Cellular Systems at the Forefront of Peripheral Nerve Regeneration

“…The quality and speed of nerve regeneration is improved when occurring in a well-vascularized site and in the presence of small amounts of scar tissue. Besides mechanical factors, the time elapsed between injury and complete repair and its functional recuperation prognosis depend on factors such as the age of the patient, the type of nerve, the site of the nerve that was injured, the cause of the injury and effect on neighboring tissues resulting from the injury [1,2,41,42]. Nonetheless, even when endogenous repair mechanisms are effective, regenerated nerves often present thinner myelin sheets and shorter nodal lengths and result in functional deficits [43].…”

Ladder-Shaped Ion Channel Ligands: Current State of Knowledge

“…P-CTX-1 is able to persist in mouse peripheral nerves from several hours to two months after exposure, which may explain the long duration of neurological disturbances. Evidence has shown that the persistence of P-CTX-1 in peripheral nerves inhibits both axonal regrowth after injury and reduces other capacities of peripheral neurons, resulting in delayed functional recovery [ 84 ].…”

“…Gambierol has been shown to induce augmentation of spontaneous Ca 2+ oscillations in cerebrocortical neurons as a consequence of K v channel inhibition. Interestingly, gambierol in these cells produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal K + -channel inhibitor [ 123 ], in contrast to the abovementioned inhibitory effect of P-CTX-1 in axotomized peripheral neurons [ 84 ].…”