Efficacy of a novel drug, zonisamide, in the modulation of oxidative stress in Parkinson's disease

Abstract

Background: Urinary 8-hydroxy-2 0 -deoxyguanosine is frequently used as an index of cytotoxicity, particularly for oxidative stress. Current research shows that urinary 8-hydroxy-2 0 -deoxyguanosine levels increase with age, disease duration and severity in patients with Parkinson's disease. In particular, a previous study reported that 8-hydroxy-2 0 -deoxyguanosine levels were increased in patients with hallucinations. Aim: Urinary 8-hydroxy-2 0 -deoxyguanosine levels were investigated as an indicator of clinical progression of Parkinson's disease. Urinary 8-hydroxy-2 0 -deoxyguanosine was examined in association with oxidative stress, in addition to modification by drug administration. Methods: We recruited 122 patients with Parkinson's disease (mean age 66.9 AE 7.9 years; severity [Hoehn and Yahr scale] 2.2 AE 0.9). Data obtained from 73 patients who underwent long-term analysis of urinary 8-hydroxy-2 0 -deoxyguanosine levels for at least two consecutive years were used for longitudinal analysis. Changes in urinary 8-hydroxy-2 0 -deoxyguanosine levels were used as a disease biomarker, while Hoehn and Yahr stage was used as an indicator of severity. Results: Baseline urinary 8-hydroxy-2 0 -deoxyguanosine levels were found to significantly correlate with age at examination, Hoehn and Yahr stage, scores on the total Unified Parkinson's Disease Rating Scale, and part 1.2 (hallucinations). In patients received dopamine agonists, changes in Hoehn and Yahr stage and urinary 8-hydroxy-2 0 -deoxyguanosine were significant over 1 year, indicating a worsening of pathology. In zonisamide-treated patients, urinary 8-hydroxy-2 0 -deoxyguanosine levels usually decreased. Conclusion: In Parkinson's disease patients, oxidative stress correlates with disease progression. As studies suggest zonisamide inhibits neuronal cell death, our results support a possible role for zonisamide in the suppression of oxidative stress in Parkinson's disease.

Efficacy and Safety of Zonisamide in Dementia with Lewy Bodies Patients with Parkinsonism: A Post Hoc Analysis of Two Randomized, Double-Blind, Placebo-Controlled Trials

“…To reduce inter-/intra-rater variability, training was conducted prior to the trial start. A more detailed analysis of the effects of zonisamide on the following four motor symptoms [31] was also performed: tremor (items 20, 21), rigidity (item 22), bradykinesia (items [23][24][25][26]31), and postural instability/gait disturbance (PIGD) (items 29,30). For each individual motor symptom, patients with zero or missing values throughout the trial were excluded from the analysis.…”

“…The proposed pharmacologic mechanisms responsible for the antiparkinsonian activity of zonisamide include both dopaminergic (activation of dopamine synthesis and release [21] and inhibition of monoamine oxidase-B [22]) and non-dopaminergic (blockade of sodium channels [23] and T-type calcium channels [24]) functions. In addition, neuroprotective effects of zonisamide have been reported [25][26][27].…”

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

“…With regard to antioxidative action, ZNS scavenges free radicals of hydroxyl and nitric oxide [35] and can suppress nitric oxide synthase activity [36] and lipid peroxide formation [37]. 8-hydroxy-20-deoxyguanosine (8-OHdG) is a biomarker for oxidative stress, and urinary 8-OHdG levels were decreased in ZNS-treated PD patients [38]. These previous studies revealed that ZNS is a multifunctional and neuroprotective drug for several kinds of neuronal diseases [15][16][17][18][23][24][25][26][27][30][31][32][33][34][35][36][37][38].…”

Evaluation of Medicinal Effects of Isoxazole Ring Isosteres on Zonisamide for Autism Treatment by Binding to Potassium Voltage-Gated Channel Subfamily D Member 2 (Kv 4.2)

“…Zonisamide later received its FDA approval as an adjuvant treatment for partial seizures in 2000. Over the years, the ameliorative effect of this drug in both partial and generalized seizures [2][3][4][5][6][7] as well as several other neurological disorders namely, psychotic conditions [8], Parkinson disease [9][10][11][12][13], neuropathic pain [14] and essential tremor [15] have been investigated. Although the precise mechanism of Zonisamide has not yet fully understood, blockage of voltagegated sodium channels and T-type calcium channels seems to be the principle route of action.…”