Berberine suppresses apoptosis and extracellular matrix (ECM) degradation in nucleus pulposus cells and ameliorates disc degeneration in a rodent model

Abstract

Intervertebral disc degeneration (IVDD) is a chronic disease with complicated pathology involving nucleus pulposus (NP) cell apoptosis and extracellular matrix (ECM) degradation. Previous studies have shown that moderate autophagy has a protective effect against apoptosis in NP cells. Berberine (BBR) is an alkaloid compound with many beneficial properties including antimicrobial, anti-inflammatory, antioxidative, and anti-apoptotic activity. Recently, it was found to induce autophagy in various tissues as well. Thus, we hypothesized that BBR may exert a therapeutic effect on IVDD through autophagy activation. In this study, we investigated the effects of BBR on IVDD and delineated a potential mechanism. BBR treatment in vitro inhibited the expression of pro-apoptotic proteins induced by tert-butyl hydroperoxide (TBHP), and increased the expression of anti-apoptotic Bcl-2. Furthermore, it prevented ECM degradation by inhibiting the production of matrix-degrading enzymes. Additionally, BBR treatment significantly activated autophagy in NP cells. However, autophagy inhibition markedly suppressed BBR's effects on NP cell apoptosis and ECM degeneration, indicating that autophagy activation with BBR treatment is protective against IVDD. In vivo, BBR treatment increased the expression of LC3 in disc cells and prevented the development of IVDD in a needle puncture-induced rat model. Thus, BBR stimulates autophagy as a protective mechanism against NP cell apoptosis and ECM degeneration, revealing its therapeutic potential in the treatment of IVDD.

Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

“…The animal experimental protocols were approved by the Animal Experimentation Committee of Huazhong University of Science and Technology. Sprague-Dawley rats (3 months old) were obtained from the Laboratory Animal Center of Huazhong University of Science and Technology (Wuhan, China) and divided randomly into three groups (control, IDD, and CUR groups); the animals in the IDD and CUR groups underwent IVD puncture surgery, which was performed using a needle (27G) on the experimental-level rat tail disc (Co7/8) according to the surgical methods reported by Chen et al [30]. After surgery, the CUR group was injected intraperitoneally with 100 mg/kg CUR and the IDD group was injected with saline twice weekly for one month.…”

Cyclin-Dependent Kinase 9 (CDK9) Inhibitor Atuveciclib Suppresses Intervertebral Disk Degeneration via the Inhibition of the NF-κB Signaling Pathway

“…Hence, for the first time, our study demonstrated that treatment with a CDK9 inhibitor (atuveciclib) disrupted the IL-1β-stimulated inflammatory response, which subsequently attenuated ECM degradation in NP cells under stress. ECM is produced by NP cells and is the main component of the gelatinous NP tissue (Chen et al, 2018). Inflammatory cytokines, such as IL-1β and TNF-α, stimulate the expression of ECM catabolic enzymes, but inhibit that of ECM matrix (Le Maitre et al, 2007;Wang et al, 2011).…”

“…IVD degeneration (IVDD) is characterized by a homeostatic imbalance between anabolism and catabolism, including extracellular matrix (ECM) degradation and nucleus pulposus (NP) cell death, eventually leading to endplate sclerosis, loss of intervertebral height, and osteophyte formation (Zhao et al, 2005;Galbusera et al, 2011;Rao et al, 2016). ECM is produced by NP cells, and is the main component of the gelatinous NP tissues (Chen et al, 2018). ECM metabolism in NP cells is a dynamic process, which includes ECM anabolism and catabolism (Wang et al, 2019).…”

Small molecule-based treatment approaches for intervertebral disc degeneration: Current options and future directions

“…The protective effect of berberine by inhibiting NF-κB activation has been shown on IL-1β stimulated human NP cells undergoing apoptosis 70 . The modulatory effects of berberine on the expression levels of anti-apoptotic protein (Bcl-2), activation of caspase 3, pro-apoptotic Bax, Bak, and release of cytochrome c have also been reported 71 .…”