Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit

Abstract

Consumption of fish containing ciguatera toxins or ciguatoxins (CTXs) causes ciguatera fish poisoning (CFP). In some patients, CFP recurrence occurs even years after exposure related to CTXs accumulation. Pacific CTX-1 (P-CTX-1) is one of the most potent natural substances known that causes predominantly neurological symptoms in patients; however, the underlying pathogenies of CFP remain unknown. Using clinically relevant neurobehavioral tests and electromyography (EMG) to assess effects of P-CTX-1 during the 4 months after exposure, recurrent motor strength deficit occurred in mice exposed to P-CTX-1. We detected irreversible motor strength deficits accompanied by reduced EMG activity, demyelination, and slowing of motor nerve conduction, whereas control unexposed mice fully recovered in 1 month after peripheral nerve injury. Finally, to uncover the mechanism underlying CFP, we detected reduction of spontaneous firing rate of motor cortical neurons even 6 months after exposure and increased number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Increased numbers of motor cortical neuron apoptosis were detected by dUTP-digoxigenin nick end labeling assay along with activation of caspase 3. Taken together, our study demonstrates that persistence of P-CTX-1 in the nervous system induces irreversible motor deficit that correlates well with excitotoxicity and neurodegeneration detected in the motor cortical neurons.

Report of the Expert Meeting on Ciguatera Poisoning

“…It induced decreased body weight, reduced food consumption, and severe visceral pain after 5 h exposure was observed, mimicking the clinical gastrointestinal symptoms noted in patients with acute ciguatera poisoning, especially visceral allodynia and hyperalgesia. Neurotoxicity was also observed (Asthana et al, 2018). The toxin nomenclature used in this table and toxin synonyms are described in Section 1 of the current report.…”

Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression

“…Functional MRI studies show that there is a remarkable long-term effect of DBS on structural and functional connectivity (brain rewiring or neuroplasticity) 73 . Our electrophysiology data showed that DBS of DCN normalized aberrant neural firing leading to complete motor recovery in ataxia mice after a single and multiple SNC, whereas we performed DCN-DBS for 21 consecutive days which is the time period for active axon regeneration and function recovery 1 , 7 , 37 , 74 . Therefore, we show that an abnormal pattern of activity that is transmitted from Purkinje cells downstream to the DCN in ataxia mice can be restored for better motor recovery from PNI.…”

“…Promoting spinal plasticity by chondroitinase improve recovery of forelimb function after PNI 15 . Our work on the single and multiple SNC, that adult mice usually take 4–8 weeks to regain full motor function 1 , 7 , 37 , 74 , suggests that disruption of cerebellar circuitry leads to permanent motor deficits. This raise the intriguing possibility that the major cause of motor deficits in patients with cerebellar disorders might not be the diseases themselves but perhaps the unrecognized PNI sustained by the patients.…”

“…1e ). Motor function recovery was further validated by electromyography (EMG) recording 6 , 7 , 37 showing decreased compound muscle action potential amplitude (CMAP) in proximal (gastrocnemius) and distal (interosseous) plantar muscles of ataxia mice at weeks 2, 3 and 4 after injury. The EMG activities of ataxia mice dropped to 77.7% (gastrocnemius) and 69.5% (interosseous) of the baseline values, and the controls were fully recovered in both proximal (Fig.…”

Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis

“…However, another study showed a recurrent motor strength deficit associated with neuronal apoptosis, reduced spontaneous firing rate and astrogliosis in the motor cortex 4 to 6 months after intraperitoneal administration of twice the same dose. The pinprick sensory test, which assesses functions of subpopulations of A-fibers and to a lesser extent C-fibers, showed no change in mice during 4 months following P-CTX-1 exposure compared with mice exposed to P-CTX-1 vehicle [ 211 ].…”