Significant effects of 4-aminopyridine and tetraethylammonium in the treatment of 6-hydroxydopamine-induced Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterizing by degeneration of dopaminergic neurons in the nigrostriatal pathway. The discovery of levodopa revolutionized the treatment of PD however, after several years of treatment most patients develop involuntary movements which significantly impair the quality of life. 4-Aminopyridine (4-AP) and tetraethylammonium (TEA) are wide-spectrum potassium channel blockers which based on the animal model studies and clinical trials have beneficial effects in treatment of several neurological disorders such as ataxia, Alzheimer disease and multiple sclerosis. Current study investigates effect of these blockers in the treatment of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. After surgical injection of 6-OHDA into medial forebrain bundle, behavioral tests were performed in the 2nd and 3rd weeks post-surgery. Only animals which showed more than 100 apomorphine-induced rotations/1 h in the 3rd week were selected for evaluation of the blocker effects. Statistical analysis of results from rotational test shows that application of high dose of 4-AP (1 mg/kg) and moderate dose of TEA (2 mg/kg) attenuate behavioral symptoms of the Parkinsonism while high dose of TEA (5 mg/kg) and application both 4-AP and TEA exacerbates these symptoms. Results from elevated body swing test confirmed the effects of TEA but not 4-AP on the rotational test. However, experiments performed on the partial Parkinsonian rats show that application of high dose of TEA attenuates apomorphine-induced rotational asymmetry significantly. Our findings indicating TEA and 4-AP could have significant effects in attenuation of PD symptoms but these effects are sensitive to dose and degree of severity of PD.

. Time schedule of animal experiments. Animals were tested by apomorphine-induced rotational and elevated body swing test (EBST) tests at 3 times before application of the blockers: Before the injection of the 6-hydroxydopamine (6-OHDA) and in the 2nd and 3rd weeks post-surgery. One day after 2nd post-surgery test, animals first received 4-aminopyridine (4-AP) or tetraethylammonium (TEA) or a cocktail containing both 4-AP and TEA intraperitoneally. 25 min after application of the blocker, EBST was performed. 5 min after EBST, apomorphine was injected and number of rotations were counted. MFB: medial forebrain bundle.Figure optionsDownload high-quality image (83 K)Download as PowerPoint slideHighlights
► 4-Aminopyridine at dose of 1 mg/kg attenuates behavioral symptoms of 6-OHDA-induced Parkinson's disease.
► Tetraethylammonium at dose of 2 mg/kg attenuates behavioral symptoms of 6-OHDA-induced Parkinson's disease.
► Tetraethylammonium at dose of 5 mg/kg exacerbates behavioral symptoms of 6-OHDA-induced Parkinson's disease.
► Tetraethylammonium at dose of 5 mg/kg attenuates behavioral symptoms of partial 6-OHDA-induced Parkinson's disease.
► Application of a cocktail containing both 4-aminopyridine and tetraethylammonium exacerbates behavioral symptoms of 6-OHDA-induced Parkinson's disease.