Barbigerone attenuates 3-nitropropionic acid-induced Huntington's disease-like neuropathology in rats via antioxidant, anti-inflammatory, and neuroprotective mechanisms

Abstract

Huntington's Disease (HD), a neurodegenerative disease characterized by motor and cognitive impairments, arises from genetic mutations causing protein aggregation within the brain. The 3-Nitropropionic acid (3-NPA) rat model mimics key features of HD. This study explored the therapeutic efficacy of barbigerone, a compound with antioxidant and anti-inflammatory properties, in ameliorating 3-NPA-induced neurodegeneration and cognitive deficits in rats. Male Wistar rats were randomized into four groups: a normal control group, a 3-NPA control group, and two groups treated with different doses of barbigerone along with 3-NPA. Behavioral test, biochemical assays, and histopathological examinations were performed. Barbigerone significantly (P < 0.0001) restored motor coordination, grip strength, and mobility compared to 3-NPA-induced HD rats. Barbigerone concomitantly reduced oxidative stress by lowering malondialdehyde (MDA) and nitric oxide (NO) levels, while enhancing antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Furthermore, treatment modulated the pro-inflammatory cytokines, suggesting a reduction in neuroinflammation. Barbigerone significantly (P < 0.0001) impacted changes in acetylcholinesterase (AChE) activity and modulated levels of key neurotransmitters, such as acetylcholine (ACh), norepinephrine (NE), serotonin (5-HT), gamma-aminobutyric acid (GABA), dopamine (DA), and glutamate (GLU). Additionally, barbigerone effectively attenuated the 3-NPA-induced elevation of caspase-3 and caspase-9, while upregulating brain-derived neurotrophic factor (BDNF), which is crucial for neuronal survival and cognitive function. Histopathological examination revealed that barbigerone significantly restored the altered striatal architecture, indicating a protective effect against neurodegeneration. Barbigerone exhibits potential as a therapeutic choice for HD, offering the possibility of alleviating motor impairments, oxidative stress, inflammation, and cognitive dysfunction.

Keywords: 3-Nitropropionic acid; Barbigerone; Cognitive function; Huntington’s disease; Motor deficits; Neuroprotective; Oxidative stress.

Fig. 1

Chemical structure of barbigerone.

Fig. 2

Experiment design.

Fig. 3

(A-D) Outcome of barbigerone on the behavioral assessment in HD rats. (A) Grip strength, (B) rotarod test, (C) open-field tests, (D) narrow beam walk test. Data are presented as mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 4

Outcome of the barbigerone on the level of AChE in rats. Results are expressed as mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, ***P < 0.001 vs. 3-NPA.

Fig. 5

(A-F) Outcome of barbigerone on neurotransmitter (A) ACh, (B) DA, (C) NE, (D) 5-HT, (E) GABA, and (F) GLU levels. Values are expressed in mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 5

(A-F) Outcome of barbigerone on neurotransmitter (A) ACh, (B) DA, (C) NE, (D) 5-HT, (E) GABA, and (F) GLU levels. Values are expressed in mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 6

(A-B) Outcome of barbigerone on mitochondrial respiratory chain enzyme activity, as assessed by (A) ATP and (B) SDH levels. Results are expressed as mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 7

(A-D) Outcome of barbigerone in the regulation of proinflammatory indicators (A) IL-1β, (B) IL-6, (C) TNF-α, and (D) NF-κB. Values are expressed in mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 8

(A–C) Outcome of barbigerone on the various antioxidant enzymes such as (A) SOD, (B) CAT, and (C) GSH. Results are expressed as mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 9

(A-B) The impact of barbigerone on markers of (A) MDA and (B) NO. Values are expressed in mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 10

(A-C) Outcome of barbigerone on key apoptotic and BDNF markers, namely (A) Caspase-3, (B) Caspase-9, and (C) BDNF. Values are expressed in mean ± S.E.M. (n = 6). A one-way ANOVA followed by Tukey’s post hoc test. #P < 0.001 vs. control; *P < 0.05, **P < 0.01, ***P < 0.001 vs. 3-NPA.

Fig. 11

(A-D) Histopathological examination of the striatum showing the effect of barbigerone on 3-NP-induced HD rat models. The black arrow shows severe degeneration in the striatum, and the blue arrows show moderate to mild degeneration in the striatum.

Fig. 12

Proposed mechanism of barbigerone on 3-NP-induced rats.