Protein kinase C is involved in the neuroprotective effect of berberine against intrastriatal injection of quinolinic acid-induced biochemical alteration in mice.

Peng Liu,Tianyan Chi,Danyang Liu,Yinjie Li,Libo Zou,Jia Xu,Xuefei Ji,Xiaoxiao Qi,Han Liu

doi:10.1111/jcmm.14522

Abstract

Protein kinase C (PKC) shows a neuronal protection effect in neurodegenerative diseases. In this study, we test whether berberine has a positive effect on the activity of PKC in quinolinic acid (QA)‐induced neuronal cell death. We used intrastriatal injections of QA mice model to test the effect of berberine on motor and cognitive deficits, and the PKC signalling pathway. Treatment with 50 mg/kg b.w of berberine for 2 weeks significantly prevented QA‐induced motor and cognitive impairment and related pathologic changes in the brain. QA inhibited the phosphorylation of PKC and its downstream molecules, GSK‐3β, ERK and CREB, enhanced the glutamate level and release of neuroinflammatory cytokines; these effects were attenuated by berberine. We used in vivo infusion of Go6983, a PKC inhibitor to disturb PKC activity in mice brain, and found that the effect of berberine to reverse motor and cognitive deficits was significantly reduced. Moreover, inhibition of PKC also blocked the anti‐excitotoxicity effect of berberine, which is induced by glutamate in PC12 cells and BV2 cells, as well as anti‐neuroinflammatory effect in LPS‐stimulated BV2 cells. Above all, berberine showed neuroprotective effect against QA‐induced acute neurotoxicity by activating PKC and its downstream molecules.

Highlights

Berberine has been showed to attenuate cognitive deficits in de‐ mentia animal models and improving motor deficits in Parkinson’s disease animal models.[24,25]. These positive effects in cognitive and motor behaviour are regulated by many factors, such as a decrease in ROS, neuron and synapse apoptosis
Jiang et al first reported that berberine could attenuate motor impairment and prolong the survival of transgenic N171‐82Q Huntington’s disease (HD) mice.[5]
The injection of quinolinic acid (QA) into the striatum of rodent or primate models is frequently used to evaluate the abil‐ ity of candidate compounds in minimizing the striatal lesion and preventing motor and cognitive deficits that are associated with HD pathogenesis.[26]

Summary

| MATERIALS AND METHODS

Berberine hydrochloride (purity ≥98%) was purchased from Dalian Meilun Biotechnology Co., Ltd. and dissolved in double‐distilled water. The PI for novel object B was decreased in the QA group (F(3, 36) =4.895, P < 0.01, post hoc, P < 0.01, Figure 1C), indicating that QA injection impaired memory recall and visual recognition. Compared with QA + berberine group, the positive effect of berberine on mice in rotarod test and novel object recognition test was partially blocked by Go 6983 infusion (Latency to fall val‐ ues: P < 0.01; PI for 1 hour: P < 0.05, Figure 2A‐C). Go6983, a PKC inhibitor, partly blocked the neuroprotective effect of berber‐ ine (cell viability: 1 μmol/L, 55.19 ± 2.95%; 2.5 μmol/L, 64.18 ± 7.16%; 5 μmol/L, 63.09 ± 7.33%, Figure 6B), but with no significance. Berberine decreased TNF‐ɑ and IL‐1β level in BV2 cells This protective effect was partly blocked by Go6983 (a PKC inhibitor), but with no significance (Figure 6C‐F).

| DISCUSSION

Findings

CONFLICT OF INTEREST