Preparation and Characterization of Sustained Release Matrix Tablets of Tizanidine Hydrochloride for Spinal Injuries

Purpose: To formulate matrix type sustained-release (SR) tablets of tizanidine hydrochloride (TH) for prolonged drug release and improvement in motor activity after spinal injuries.Methods: Matrix tablets were prepared by the wet granulation method using four polymers (hydroxyl propyl methyl cellulose [HPMC] K 100, ethyl cellulose [EC], guar gum, and polyvinylpyrrolidone (PVP K30) and characterized for hardness, friability, drug content, swelling, weight variation, in vitro drug release, and in vivo motor function activity using the spinal injury rat model.Results: All tablets showed good drug content, hardness, and other physicochemical properties. The tablet formulations showed a percent drug release ranging from 92.54 ± 1.02 to 98.56 ± 1.26 % at the end of 12 h. Using the spinal injury rat model, negative control had a motor activity of only 12.75 %, while F4 (containing HPMC, EC, and PVP) and F5 (containing EC, guar gum, and PVP) had motor activities of 62.25% and 57.5%, respectively, compared with 68.0 % for normal controls.Conclusion: SR matrix tablets of TH showed significant improvement in motor activity in post-traumatic spinal injury rat model.Keywords: Sustained release tablet, Spinal injuries, Matrix tablet, Tizanidine hydrochlorid

Sanguinarine Attenuates Neuropathic Pain in a Rat Model of Chronic Constriction Injury

Objective. There is still no effective treatment of neuropathic pain. Sanguinarine is a natural plant medicine with anti-inflammatory effects, but its effect on neuropathic pain remains unclear. This study was aimed at investigating the potential of sanguinarine to attenuate neuropathic pain. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Rats were randomly divided into several groups: sham, CCI, CCI+SG (1.00 mg/kg), CCI+SG (2.50 mg/kg), and CCI+SG (6.25 mg/kg). SG was injected intraperitoneally from the day of surgery every three days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded before surgery and on days 1, 3, 7, and 14 after surgery. The microglia in the spinal dorsal horn were examined by immunofluorescence. p38 MAPK expression in the spinal dorsal horn was detected by PCR and Western blot analysis. Cytokine levels in the spinal dorsal horn were measured by ELISA. Results. MWT and TWL were significantly reduced in the CCI group, but sanguinarine recovered MWT and TWL in the CCI group. In addition, sanguinarine inhibited the activation of microglia and decreased the expression of p-p38 and TNF-α, IL-1β, and IL-6 in the spinal dorsal horn of the CCI group in a dose-dependent manner. Conclusions. Our results suggest that sanguinarine can attenuate neuropathic pain via inhibiting the activation of microglia and the activation of the p38 MAPK signaling pathway

Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats

P2X4 and P2X7 receptors play an important role in neuropathic pain after spinal cord injury. Regulation of P2X4 and P2X7 receptors can obviously reduce pain hypersensitivity after injury. To investigate the role of neural stem cell transplantation on P2X receptor-mediated neuropathic pain and explore related mechanisms, a rat model of spinal cord injury was prepared using the free-falling heavy body method with spinal cord segment 10 as the center. Neural stem cells were injected into the injured spinal cord segment using a micro-syringe. Expression levels of P2X4 and P2X7 receptors, neurofilament protein, and glial fibrillary acidic protein were determined by immunohistochemistry and western blot assay. In addition, sensory function was quantitatively assessed by current perception threshold. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess neuropathological pain. The results showed that 4 weeks after neural stem cell transplantation, expression of neurofilament protein in the injured segment was markedly increased, while expression of glial fibrillary acidic protein and P2X4 and P2X7 receptors was decreased. At this time point, motor and sensory functions of rats were obviously improved, and neuropathic pain was alleviated. These findings demonstrated that neural stem cell transplantation reduced overexpression of P2X4 and P2X7 receptors, activated locomotor and sensory function reconstruction, and played an important role in neuropathic pain regulation after spinal cord injury. Therefore, neural stem cell transplantation is one potential option for relieving neuropathic pain mediated by P2X receptors

Cyanidin suppresses amyloid beta-induced neurotoxicity by inhibiting reactive oxygen species-mediated DNA damage and apoptosis in PC12 cells

Amyloid beta (Aß)-induced oxidative stress is a major pathologic hallmark of Alzheimer′s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aß-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aß-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aß, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aß-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aß-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aß neurotoxicity

Injectable and Degradable POSS–Polyphosphate–Polysaccharide Hybrid Hydrogel Scaffold for Cartilage Regeneration

The limited self-repair capacity of articular cartilage has motivated the development of stem cell therapy based on artificial scaffolds that mimic the extracellular matrix (ECM) of cartilage tissue. In view of the specificity of articular cartilage, desirable tissue adhesiveness and stable mechanical properties under cyclic mechanical loads are critical for cartilage scaffolds. Herein, we developed an injectable and degradable organic–inorganic hybrid hydrogel as a cartilage scaffold based on polyhedral oligomeric silsesquioxane (POSS)-cored polyphosphate and polysaccharide. Specifically, acrylated 8-arm star-shaped POSS-poly(ethyl ethylene phosphate) (POSS-8PEEP-AC) was synthesized and cross-linked with thiolated hyaluronic acid (HA-SH) to form a degradable POSS-PEEP/HA hydrogel. Incorporation of POSS in the hydrogel increased the mechanical properties. The POSS-PEEP/HA hydrogel showed enzymatic biodegradability and favorable biocompatibility, supporting the growth and differentiation of human mesenchymal stem cells (hMSCs). The chondrogenic differentiation of encapsulated hMSCs was promoted by loading transforming growth factor-β3 (TGF-β3) in the hydrogel. In addition, the injectable POSS-PEEP/HA hydrogel was capable of adhering to rat cartilage tissue and resisting cyclic compression. Furthermore, in vivo results revealed that the transplanted hMSCs encapsulated in the POSS-PEEP/HA hydrogel scaffold significantly improved cartilage regeneration in rats, while the conjugation of TGF-β3 achieved a better therapeutic effect. The present work demonstrated the potential of the injectable, biodegradable, and mechanically enhanced POSS-PEEP/HA hybrid hydrogel as a scaffold biomaterial for cartilage regeneration