Oxyberberine an oxoderivative of berberine confers neuroprotective effects in controlled-cortical impact mouse model of traumatic brain injury

Abstract

Background

Traumatic brain injury (TBI) is known as a silent epidemic that causes many deaths and disabilities worldwide. We examined the response of oxyberberine (OBB) in lipopolysaccharide-stimulated BV2 microglial cells and a controlled-cortical impact (CCI) mouse model of TBI.

Methods

We synthesized OBB from berberine, and also prepared OBB-nanocrystals (OBB-NC). Male C57BL/6 mice were used for CCI surgery, and post-CCI neurobehavioral deficits were assessed from 1 h after injury through 21 days post-injury (dpi).

Results

OBB treatment reduced the lipopolysaccharide-triggered elevated levels of reactive oxygen species, nitric oxide, and nuclear factor kappa B (NF-κB) in BV2 microglial cells, indicating a neuroprotective potential. CCI-operated mice exhibited significant neurological deficits on 1, 3, and 5 dpi in neurological severity scoring and rotarod assay. OBB (25 and 50 mg/kg/day) and OBB-NC (3 mg/kg/day) ameliorated these neurological aberrations. Mice subjected to CCI surgery also displayed anxiogenic- and depression-like behaviours, and cognitive impairments in forced-swimming test and elevated-zero maze, and novel object recognition task, respectively. Administration of OBB reduced these long-term neuropsychiatric complications, and also levels of toll-like receptor 4 (TLR4), high-motility group protein 1 (HMGB1), NF-κB, tumour necrosis factor-alpha and interleukin 6 cytokines in the ipsilateral cortex of mice.

Conclusion

We suggest that the administration of OBB offers neuroprotective effects via inhibition of HMGB1-mediated TLR4/NFκB pathway.

Keywords:

• Oxyberberine
• traumatic brain injury
• neuroinflammation
• BV2 cells
• HMGB1
• TLR4
• NF-κB

Acknowledgements

The authors (PMT, MRB, TP, ASS, ZR, AM, VRK and MPD) would like to thank NIPER Hyderabad for providing all the resources and DoP, Ministry of Chemicals and Fertilizers, Government of India for providing fellowship.

Authors’ contributions

PMT performed CCI surgery, behavioral work, molecular studies and prepared manuscript, MRB assisted in molecular studies, data analysis, curation and making a manuscript draft, TP helped in CCI surgery and behavioral assessment, ZR in vitro study, ASS and VRK synthesized OBB, AM and JM formulated OBB-NC, and MPD contributed to study design, data interpretation and edited the manuscript.

Data availability

The authors declare that all the data supporting the findings of this study are available within the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

IRB/ethical review

IRB review is not applicable to our study. All the experimental procedures were performed in accordance with the approved methods by Institutional Animal Ethics Committee (IAEC) of National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, India protocol number: NIP/12/2021/PC/442.

Additional information

Funding

MPD thanks DST-SERB for funding (File number SRG/2020/002439).