The Transcription Factor Nrf2 Mediates the Effects of Antrodia camphorata Extract on Neuropathological Changes in a Mouse Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD.

Figures

Figure 1

( A ). Effect of…

Figure 1

( A ). Effect of AC treatment on TH expression in substantia nigra.…

Figure 1 (A). Effect of AC treatment on TH expression in substantia nigra. MPTP group showed an extensive loss of TH neurons (A2), compared to the Sham group (A). AC treatment at the doses of 10, 30 and 100 mg/kg ((A3–A5), see score (A6)) significantly restored the number of TH neurons. Sham group treated with AC at dose of 100 mg/kg did not show any change (A1). One-way ANOVA test *** p < 0.001 vs. Sham; ### p < 0.001 vs. MPTP (A6). Effect of AC treatment on α-synuclein expression in substantia nigra (B,C). MPTP-intoxicated mice showed an increase in the number of α-syn aggregates in dopaminergic neurons (B1) compared to the Sham group (B). The neuroprotective role of AC at doses of 10, 30, and 100 mg/kg is revealed by the reduction in the number of α-syn aggregates (B2–B4). These results were confirmed by ELISA kit analysis of p-α-syn (C). One way ANOVA test *** p < 0.001 vs. Sham; # p < 0.05 vs. MPTP; ### p < 0.001 vs. MPTP (B5).

Figure 2

Effect of AC on the…

Figure 2

Effect of AC on the myelination process in substantia nigra. LFB staining showed…

Figure 2 Effect of AC on the myelination process in substantia nigra. LFB staining showed a significant loss of myelin in MPTP group (B) compared to the Sham group (A). The treatment with AC at doses of 10, 30, and 100 mg/kg (C–E) significantly restored the myelin presence. One-way ANOVA test *** p < 0.001 vs. Sham; ## p < 0.01 vs. MPTP; ### p < 0.001 vs. MPTP (F).

Figure 3

Effect of AC on GFAP,…

Figure 3

Effect of AC on GFAP, IBA-1 expression in substantia nigra. Midbrain section of…

Figure 3 Effect of AC on GFAP, IBA-1 expression in substantia nigra. Midbrain section of MPTP-injected mice showed high expression of GFAP (A1) and IBA-1 (B1), compared to the Sham groups (A,B). GFAP and IBA-1 expression significantly decreased after AC treatments, especially at doses of 30 and 100 mg/kg (A3,A4,B3,B4). AC treatment at dose of 10 mg/kg (A2,B2). One way ANOVA test *** p < 0.001 vs. Sham; # p < 0.05 vs. MPTP; ### p < 0.001 vs. MPTP (A5,B5).

Figure 4

Effect of AC on NF-kB…

Figure 4

Effect of AC on NF-kB pathway and pro-inflammatory cytokine levels. Western blot analysis…

Figure 4 Effect of AC on NF-kB pathway and pro-inflammatory cytokine levels. Western blot analysis showed an important modulation of NF-kB (A), IkBα (B), and also of pro-inflammatory cytokines, such as IL-1β (C), TNF-α (D), COX-2 (E), and iNOS (F). One-way ANOVA test ** p < 0.01 vs. Sham; *** p < 0.001 vs. Sham; # p < 0.05 vs. MPTP; ## p < 0.01 vs. MPTP; ### p < 0.001 vs. MPTP.

Figure 5

Antioxidant effect of AC. Western…

Figure 5

Antioxidant effect of AC. Western blot analysis showed an important modulation of MnSOD…

Figure 5 Antioxidant effect of AC. Western blot analysis showed an important modulation of MnSOD (A), HO-1 (B), and Nrf2 (C). ELISA kit showed an increase of ROMO1 levels (D) and a decrease of GSH (E) levels in MPTP group compared to the Sham group; AC restored their levels. One way ANOVA test * p < 0.05 vs. Sham; *** p < 0.001 vs. Sham; # p < 0.05 vs. MPTP; ## p < 0.01 vs. MPTP; ### p < 0.001 vs. MPTP.