a-neuronal-apoptosis-model-induced-by-spinal-cord-compression-in-rat

A Neuronal Apoptosis Model induced by Spinal Cord Compression in Rat

As a severe progressive degenerative disease, cervical spondylotic myelopathy (CSM) has a poor prognosis and is associated with physical pain, stiffness, ...

Shanghai University of Traditional Chinese Medicine

Oleanolic acid (OA) and its glycosides have been reported to prevent bone loss by inhibiting the formation of osteoclasts. However, because bone formation and resorption are balanced processes in bone metabolism, no studies have described the effect of OA on osteogenesis. The aim of the present study was to evaluate the osteoprotective effect of OA in rats with ovariectomy (OVX)-induced osteoporosis and to search for the molecular targets of OA in bone mesenchymal stem cells (bMSCs).

Oleanolic acid exerts an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulates the osteoblastic differentiation of bone mesenchymal stem cells in vitro.

Osteoarthritis (OA) is the most common form of joint disease. OA frequently affects knees, hips, hands, and the spine. It is characterized by the progressive destruction of articular cartilage and subchondral bone accompanied by low-grade inflammation that together result in pain and deformity. Recent studies have shed light on the nature of OA genetic susceptibility and confirmed a number of candidate genes involved in the destruction of the synovium, articular cartilage, and subchondral bone in OA pathogenesis. During the progression of OA, there are several cellular changes in joints, including an increase in the number of activated osteoclasts and macrophages and an infiltration of the synovium by activated T-cells and B-cells. Pro-inflammatory mediators (e.g. interleukin IL-1, IL-1beta, IL-6, IL-17, and IL-18, and Tumor necrosis actor-alpha), proteinases (e.g. matrix metalloproteinase 9 and cathepsin K), and regulators of cartilage and bone formation (e.g. BMPs) have been shown to have important roles in OA progression at the molecular level. Studies have suggested that OA shares several common characteristics with rheumatoid arthritis (RA). To systematically understand OA, this review summarizes OA disease genes, mouse models of human disease experimental mouse models, mechanisms of OA pathogenesis, and current OA therapies.

Osteoarthritis: genetic factors, animal models, mechanisms, and therapies.

Icariin (ICA) is an active component of Herba Epimedium effective in preventing osteoporosis. Bone mesenchymal stem cells (bMSCs) are an important target by which ICA promotes osteogenesis. However, its molecular mechanisms are poorly defined. In the present study, we induced osteoporosis in rats by corticosterone (CORT) and ovariectomy (OVX), treated both with ICA for 2 weeks or 3 months. As results, both models displayed bone loss tendency within 2 weeks and a significant bone loss after 3 months. ICA promoted bMSCs diffenentiation from CORT rat, and increased the secretion of osteocalcin, collagen I, runt-related transcription factor 2 in OVX model. Gene profile revealed a marked shift of gene expression by ICA, with much more significance in CORT rats. These potential molecular targets were involved in cell communication, adhesion, cycle and cytokines secretion. But very few genes overlapped in these two models, suggesting the effects and molecular mechanisms of ICA on osteoporosis might be pathogenesis-dependent. However, the Notch signaling pathway was common in both models, and should be paid close attention to for further study.

Different molecular targets of Icariin on bMSCs in CORT and OVX -rats.

Psoralea corylifolia extract has been reported to promote bone formation in osteoporotic animals. Psoralen (PSO), a flavonoid glycoside, as the active component of P corylifolia L, is effective in increasing new bone-forming osteoblasts in parietal bone defects. However, the effect and molecular mechanisms of PSO on bone mesenchymal stem cells (bMSCs) in the osteoporotic state are widely unknown. This study was designed to evaluate the osteoprotective effect of PSO in ovariectomy (OVX)-induced rats and to seek possible molecular mechanisms of PSO in bMSCs.

The osteoprotective effect of psoralen in ovariectomy-induced osteoporotic rats via stimulating the osteoblastic differentiation from bone mesenchymal stem cells.

Most chronic low back pain is the result of degeneration of the lumbar intervertebral disc. Ligustrazine, an alkaloid from Chuanxiong, reportedly is able to relieve pain, suppress inflammation, and treat osteoarthritis and it has the protective effect on cartilage and chondrocytes. Therefore, we asked whether ligustrazine could reduce intervertebral disc degeneration. To determine the effect of ligustrazine on disc degeneration, we applied a rat model. The intervertebral disc degeneration of the rats was induced by prolonged upright posture. We found that pretreatment with ligustrazine for 1 month recovered the structural distortion of the degenerative disc; inhibited the expression of type X collagen, matrix metalloproteinase (MMP)-13, and MMP3; upregulated type II collagen; and decreased IL-1 β , cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression. In conclusion, ligustrazine is a promising agent for treating lumbar intervertebral disc degeneration disease. 

Protective effect of ligustrazine on lumbar intervertebral disc degeneration of rats induced by prolonged upright posture.

High incidences of neck pain morbidity are challenging in various situations for populations based on their demographic, physiological and pathological characteristics. Chinese proprietary herbal medicines, as Complementary and Alternative Medicine (CAM) products, are usually developed from well-established and long-standing recipes formulated as tablets or capsules. However, good quantification and strict standardization are still needed for implementation of individualized therapies. The Qishe pill was developed and has been used clinically since 2009. The Qishe pill's personalized medicine should be documented and administered to various patients according to the ancient TCM system, a classification of personalized constitution types, established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of the Qishe pill and compare its metabolic rate in the three major constitution types (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges to individualized standardized TCM.

Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized controlled trial.

Ligustroflavone is one major compound contained in active fraction from Fructus Ligustri Lucidi (the fruit of Ligustrum lucidum), which could regulate parathyroid hormone (PTH) levels and improve calcium balance by acting on calcium-sensing receptors (CaSR). This study aimed to explore the potency of ligustroflavone as a CaSR antagonist and its protective effects against diabetic osteoporosis in mice. LF interacted well with the allosteric site of CaSR shown by molecular docking analysis, increased PTH release of primary parathyroid gland cells and suppressed extracellular calcium influx in HEK-293 cells. The serum level of PTH attained peak value at 2  h and maintained high during the period of 1  h and 3  h than that before treatment in mice after a single dose of LF. Treatment of diabetic mice with LF inhibited the decrease in calcium level of serum and bone and the enhancement in urinary calcium excretion as well as elevated circulating PTH levels. Trabecular bone mineral density and micro-architecture were markedly improved in diabetic mice upon to LF treatment for 8 weeks. LF reduced CaSR mRNA and protein expression in the kidneys of diabetic mice. Taken together, ligustroflavone could transiently increase PTH level and regulate calcium metabolism as well as prevent osteoporosis in diabetic mice, suggesting that ligustroflavone might be an effective antagonist on CaSR.

Protective Effects of Ligustroflavone, an Active Compound from Ligustrum lucidum, on Diabetes-Induced Osteoporosis in Mice: A Potential Candidate as Calcium-Sensing Receptor Antagonist.

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and βIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.

Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1-dependent mitochondrial fission.

Depression is partially caused by inflammation in central nervous system. This study investigated the ameliorative effects of phenol glycosides (PG) from Ligustrum lucidum Ait. (Oleaceae) on neuroinflammation and depressive-like behavior in mice hypothalamus as well as the molecular mechanism. Mice were administered with PG extract for 2 weeks prior to treatment with LPS. The mice treated with PG extract showed resistance to LPS-induced reduction in body weight and LPS-induced depressive-like behaviors shown by sucrose preference, tail suspension test, forced swimming test and open field test. LPS-induced activation of microglial cells and elevation in protein expression of inflammatory cytokines including IL-1β, RANTES and MCP-1 in hypothalamus of mice were abrogated by pre-treatment with PG extract. This extract down-regulated expression of TLR4, MyD88, NLRP3, renin and angiotensin II and decreased proportional area of Iba-1 microglias in hypothalamus. Pre-treatment with PG extract inhibited LPS-triggered activation of CaSR/G signaling, stimulated 1-OHase expression in hypothalamus, and enhanced circulating 1,25(OH) D level. Overall, pre-treatment with PG extract ameliorated LPS-induced depressive-like behaviors by repressing neuroinflammation in mice hypothalamus which was attributed to its suppression on activation of microglia and production of inflammatory cytokines via acting on TLR4 pathway, CaSR and RAS cascade associated with improving vitamin D metabolism.

Phenol glycosides extract of Fructus Ligustri Lucidi attenuated depressive-like behaviors by suppressing neuroinflammation in hypothalamus of mice.

Multipotent bone marrow stromal cells (BMSCs) are adult stem cells that form functional osteoblasts and play a critical role in bone remodeling. During aging, an increase in bone loss and reduction in structural integrity lead to osteoporosis and result in an increased risk of fracture. We examined age-dependent histological changes in murine vertebrae and uncovered that bone loss begins as early as the age of 1 mo.

Article	Year
Oleanolic acid exerts an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulates the osteoblastic differentiation of bone mesenchymal stem cells in vitro. Menopause (New York, N.Y.)\| PubMed ID: 22011754	2012
Osteoarthritis: genetic factors, animal models, mechanisms, and therapies. Frontiers in bioscience (Elite edition)\| PubMed ID: 22201856	2012
Different molecular targets of Icariin on bMSCs in CORT and OVX -rats. Frontiers in bioscience (Elite edition)\| PubMed ID: 22201948	2012
The osteoprotective effect of psoralen in ovariectomy-induced osteoporotic rats via stimulating the osteoblastic differentiation from bone mesenchymal stem cells. Menopause (New York, N.Y.)\| PubMed ID: 22781784	2012
Protective effect of ligustrazine on lumbar intervertebral disc degeneration of rats induced by prolonged upright posture. Evidence-based complementary and alternative medicine : eCAM\| PubMed ID: 24872832	2014
Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized co... Trials\| PubMed ID: 25885543	2015
Protective Effects of Ligustroflavone, an Active Compound from Ligustrum lucidum, on Diabetes-Induced Osteoporosis in Mice: A Potential Candidate as Calcium-Sensing Receptor Antagonist. The American journal of Chinese medicine\| PubMed ID: 30834778	2019
Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1-dependent mitochondrial fission. Journal of neurochemistry\| PubMed ID: 32215908	2020
Phenol glycosides extract of Fructus Ligustri Lucidi attenuated depressive-like behaviors by suppressing neuroinflammation in hypothalamus of mice. Phytotherapy research : PTR\| PubMed ID: 32603019	2020
Transcriptomic alterations underline aging of osteogenic bone marrow stromal cells. World journal of stem cells\| PubMed ID: 33584984	2021

Shu-fen Liu

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