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. 2023 May 30:14:1188470.
doi: 10.3389/fphar.2023.1188470. eCollection 2023.

Intranasal cerium oxide nanoparticles improves locomotor activity and reduces oxidative stress and neuroinflammation in haloperidol-induced parkinsonism in rats

Mohammad  1 , Urooj Ahmed Khan  2 , Musarrat Husain Warsi  3 , Huda Mohammed Alkreathy  4 , Shahid Karim  4 , Gaurav Kumar Jain  5   6 , Asgar Ali  1
Affiliations

Intranasal cerium oxide nanoparticles improves locomotor activity and reduces oxidative stress and neuroinflammation in haloperidol-induced parkinsonism in rats

Mohammad et al. Front Pharmacol. .

Abstract

Introduction: Cerium oxide nanoparticles (CONPs) have been investigated for their therapeutic potential in Parkinson's disease (PD) due to their potent and regenerative antioxidant activity. In the present study, CONPs were used to ameliorate the oxidative stress caused by free radicals in haloperidol-induced PD in rats following intranasal administration. Method: The antioxidant potential of the CONPs was evaluated in vitro using ferric reducing antioxidant power (FRAP) assay. The penetration and local toxicity of the CONPs was evaluated ex-vivo using goat nasal mucosa. The acute local toxicity of intranasal CONPs was also studied in rat. Gamma scintigraphy was used to assess the targeted brain delivery of CONPs. Acute toxicity studies were performed in rats to demonstrate safety of intranasal CONPs. Further, open field test, pole test, biochemical estimations and brain histopathology was performed to evaluate efficacy of intranasal CONPs in haloperidol-induced PD rat model. Results: The FRAP assay revealed highest antioxidant activity of prepared CONPs at a concentration of 25 μg/mL. Confocal microscopy showed deep and homogenous distribution of CONPs in the goat nasal mucus layers. No signs of irritation or injury were seen in goat nasal membrane when treated with optimized CONPs. Scintigraphy studies in rats showed targeted brain delivery of intranasal CONPs and acute toxicity study demonstrated safety. The results of open field and pole test showed highly significant (p < 0.001) improvement in locomotor activity of rats treated with intranasal CONPs compared to untreated rats. Further, brain histopathology of treatment group rats showed reduced neurodegeneration with presence of more live cells. The amount of thiobarbituric acid reactive substances (TBARS) was reduced significantly, whereas the levels of catalase (CAT), superoxide dismutase (SOD), and GSH were increased significantly, while amounts of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) showed significant reduction after intranasal administration of CONPs. Also, the intranasal CONPs, significantly high (p < 0.001) dopamine concentration (13.93 ± 0.85 ng/mg protein) as compared to haloperidol-induced control rats (5.76 ± 0.70 ng/mg protein). Conclusion: The overall results concluded that the intranasal CONPs could be safe and effective therapeutics for the management of PD.

Keywords: Parkinson disease; antioxidant activity; brain targeting; gamma scintigraphy; inorganic nanoparticles.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram showing study plan for assessment of depth of penetration using CLSM (Confocal Laser Scanning Microscopy).
FIGURE 2
FIGURE 2
Schematic diagram showing study plan for nasal cilio toxicity study.
FIGURE 3
FIGURE 3
Graphic representation of a SPECT scans of rats to validate drug accumulation and disposal in the brain.
FIGURE 4
FIGURE 4
FRAP antioxidant activity of CONPs. The significance was determined as ***p < 0.001 versus FRAP activity at 5 μg/mL.
FIGURE 5
FIGURE 5
CLSM (Confocal Laser Scanning Microscopy) photomicrographs of nasal mucosa after 6 h treatment with CONPs depicting depth analysis.
FIGURE 6
FIGURE 6
Histoptahological images of nasal goat mucosa; (A) negative control; (B) positive control and (C) treatment with CONPs. Thin arrows in figure (A) represents no nasociliary deterioration whereas, thick black arrows in figure (B) showed nasal mucosa was severely disrupted. Further, black thin arrows in figure (C) no signs of irritation or injury were observed.
FIGURE 7
FIGURE 7
Gamma scintigraphy imaging of intranasal CONPs captured at various time intervals (A) 15 min, (B) 30 min, and (C) 60 min in male Sprague Dawley rats.
FIGURE 8
FIGURE 8
Percent weight variation in healthy group and CONPs group.
FIGURE 9
FIGURE 9
Histopathological investigation of brain samples using H and E staining observed at 100× magnification with special focus on hippocampus region whereas figure (A–D) represents hippocampal region of Group 1 (negative control), Group 2 (haloperidol-induced control), Group 3 (haloperidol-induced treated with the SD drug), and Group 4 (haloperidol-induced treated with CONPs) respectively. Black arrows in figure (A) showed no lesions whereas, arrows in figure (B) represents neuronal damage. Moreover, black arrows in figure (C) showed small and scattered living cells and in figure (D) congregate live cells were observed.
FIGURE 10
FIGURE 10
Assessment of (A) TBARS, (B) GSH, (C) SOD, (D) CAT, (E) IL-6, and (F) TNF-α. (#Comparison of disease group with other groups, and *comparison of healthy group with other groups). The significance was determined to be ### p < 0.001, ## p < 0.01 and # p < 0.05 respectively, vs. disease group; ***p < 0.001, **p < 0.01 and *p < 0.05 versus healthy group respectively.
FIGURE 11
FIGURE 11
HPLC Chromatogram of dopamine by the HPLC reversed phase system. (A) Healthy Group; (B) Disease Group; (C) Treatment Group; and (D) Dopamine level in different groups. (#comparison of disease group with other groups, and *comparison of healthy group with other groups). The significance was determined as ### p < 0.001, and ## p < 0.01 versus disease group, respectively; ***p < 0.001 versus healthy group respectively.
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Grants and funding

This research work was funded by the Institutional Fund Projects under grant no. (IFPIP-1723-140-1443). Therefore, the authors gratefully acknowledge technical and financial support provided by the Ministry of Education and King Abdulaziz University, DSR Jeddah, Saudi Arabia.
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