Coadministration of 6-Shogaol and Levodopa Alleviates Parkinson's Disease-Related Pathology in Mice

Abstract

Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.

Keywords: 6-shogaol; Dopaminergic neuron; Levodopa; Neuroinflammation; Non-motor symptom; Parkinson’s disease.

Fig. 1

Effect of co-administering 6-SHO and L-dopa on motor dysfunction in MPTP/p-injected mice. To evaluate motor function, T-turn (A) and T-LA (B) in the pole test and latency to fall (C) in the rotarod test and were measured. Values are given as the mean ± SEM (N=5-8). Data were analyzed by One-way ANOVA followed by Dunnett’s multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 vs. MPTP/p group.

Fig. 2

Effect of co-administering 6-SHO and L-dopa on depression-like behaviors, olfactory and memory dysfunctions in MPTP/p-injected mice. SST (A) and TST (B) were performed to evaluate depression-like behavior. Buried food test was performed to evaluate olfactory function (C). Y-maze was performed to evaluate memory function (D). Values are given as the mean ± SEM (N=5-8). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test or Student’s t-test. *p<0.05 and **p<0.01 vs. MPTP/p group (One-way ANOVA); ^$p<0.05 vs. MPTP/p group (Student’s t-test).

Fig. 3

Effect of co-administering 6-SHO and L-dopa on dopaminergic neurons in ST of MPTP/p-injected mice. Western blot was performed to measure protein level of TH (A) and DAT (B) in the ST. Values are given as the mean ± SEM (N=5-8). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test or Student’s t-test. *p<0.05 and ***p<0.001 vs. MPTP/p group; ^$$p<0.01 vs. MPTP/p group (Student’s t-test).

Fig. 4

Effect of co-administering 6-SHO and L-dopa on expression of Iba-1 in ST and SN of MPTP/p-injected mice. Western blot was performed to measure protein level of Iba-1 in the ST (A) and SN (B). Values are given as the mean ± SEM (N=5-8). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test or Student’s t-test. *p<0.05 and **p<0.01 vs. MPTP/p group; ^$$p<0.01 vs. MPTP/p group (Student’s t-test).

Fig. 5

Effect of co-administering 6-SHO and L-dopa on expression of GFAP in ST and SN of MPTP/p-injected mice. Western blot was performed to measure protein level of GFAP in the ST (A) and SN (B). Values are given as the mean ± SEM (N=5-8). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test. *p<0.05 and **p<0.01 vs. MPTP/p group.

Fig. 6

Effect of co-administering 6-SHO and L-dopa on expression of TNF-α in ST and SN of MPTP/p-injected mice. Western blot was performed to measure protein level of TNF-α in the ST (A) and SN (B). Values are given as the mean ± SEM (N=5-8). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test or Student’s t-test. *p<0.05 vs. MPTP/p group; ^$p<0.05 vs. MPTP/p group (Student’s t-test).

Fig. 7

Summary of the mechanism of action with co-administration of 6-SHO and L-dopa. Created with BioRender.com.