Effect of the C-terminal domain of the heavy chain of tetanus toxin on dyskinesia caused by levodopa in 6-hydroxydopamine-lesioned rats

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Abstract

Recombinant Hc-TeTx fragment has been successfully assayed as a neuroprotector in Parkinson's disease (PD) models. While levodopa has been the gold standard in the therapeutic treatment of PD, unfortunately almost all patients develop dyskinesia or abnormal involuntary movements (AIMs). The aim of this study was to evaluate the effect of post-lesion treatment with Hc-TeTx or pre-lesion treatment with Hc-TeTx on levodopa-induced dyskinesia in rats. AIMs were induced with low, mid and high levodopa doses (6, 10 and 25 mg/kg respectively) and examined for 22 days. Finally, tyrosine hydroxylase-positive (TH) neurons in the substantia nigra pars compacta (SNpc) and FosB/ΔFosB expression in the striatum were examined. Hc-TeTx (20 μg/kg i.m.) co-administrated with levodopa (6 or 10 mg/kg) did not reduce the severity of the AIMs, while the group treated with Hc-TeTx plus levodopa (25 mg/kg) presented a temporary attenuation of dyskinetic limb and orolingual movements; however, the restorative effects of Hc-TeTx on motor behavior and dopaminergic neuronal death in the SNpc were not observed. There was a significant post-treatment increase in FosB/ΔFosB expression in the dorsolateral and ventral striatum of animals treated with Hc-TeTx. When Hc-TeTx was administrated prior to dopaminergic lesion and levodopa administration (10 mg/kg), there was a slight recovery of motor asymmetry, one week post-lesion. Moreover, while the Hc-TeTx slightly reduced the AIMs score in the first days of levodopa treatment, it was not effective by the end of the experiment. Also, the loss of TH neurons in the SNpc revealed that Hc-TeTx did not induce effective neuroprotection. It is worth noting that a reduction of FosB/ΔFosB expression in the dorsolateral striatum was observed. In summary, Hc-TeTx treatment did not effectively reduce the induction of AIMs by levodopa in hemiparkinsonian rats, although the pre-treatment administration of Hc-TeTx causes minor FosB expression in the dorsolateral striatum.

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