fumarates and Spinal-Cord-Injuries

Many factors contribute to the poor axonal regrowth and ineffective functional recovery after spinal cord injury (SCI). Biomaterials have been used for SCI repair by promoting bridge formation and reconnecting the neural tissue at the lesion site. The mechanical properties of biomaterials are critical for successful design to ensure the stable support as soon as possible when compressed by the surrounding spine and musculature. Poly(propylene fumarate) (PPF) scaffolds with high mechanical strength have been shown to provide firm spatial maintenance and to promote repair of tissue defects. A multichannel PPF scaffold is combined with collagen biomaterial to build a novel biocompatible delivery system coated with neurotrophin-3 containing an engineered collagen-binding domain (CBD-NT3). The parallel-aligned multichannel structure of PPF scaffolds guide the direction of neural tissue regeneration across the lesion site and promote reestablishment of bridge connectivity. The combinatorial treatment consisting of PPF and collagen loaded with CBD-NT3 improves the inhibitory microenvironment, facilitates axonal and neuronal regeneration, survival of various types of functional neurons and remyelination and synapse formation of regenerated axons following SCI. This novel treatment strategy for SCI repair effectively promotes neural tissue regeneration after transected spinal injury by providing a regrowth-supportive microenvironment and eventually induces functional improvement.

Topics: Animals; Fumarates; Nerve Growth Factors; Nerve Regeneration; Polypropylenes; Rats; Spinal Cord Injuries; Tissue Engineering; Tissue Scaffolds

Positively-charged oligo[poly(ethylene glycol)fumarate] (OPF

Topics: Animals; Axons; Fumarates; Glial Cell Line-Derived Neurotrophic Factor; Humans; Hydrogels; Nerve Regeneration; Polyethylene Glycols; Rats, Sprague-Dawley; Recovery of Function; Remyelination; Schwann Cells; Spinal Cord Injuries; Tissue Scaffolds

Spinal cord injury (SCI) causes permanent changes in motor, sensory, and autonomic functions. Unfortunately, there are no stable cures and current treatments include surgical decompression, methylprednisolone, and hemodynamic control that lead to modest function recovery. Fumaric acid esters (FAEs) were firstly used in the management of an immunological skin disorder, such as psoriasis. Because of their potent anti-inflammatory effects, they have been introduced in multiple sclerosis (MS). Investigation has shown not only an anti-inflammatory, but also supposed neuroprotective mechanism of action. The goal of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) in a mouse model of traumatic SCI. SCI was produced by extradural compression for 1 min of the spinal cord at the T6-7 level using an aneurysm clip, and DMF and MMF (both at 30 mg/kg) were administered by oral gavage to the mice 1 and 6 h after SCI. For locomotor activity, study mice were treated with FAEs once daily for 10 days. We observed that mice treated with DMF exhibited a significant and sustained recovery of motor function. FAEs significantly reduced the severity of inflammation by a modulation of pro-inflammatory cytokines and apoptosis factors, and increased neutrophic factors such as anti-brain-derived neurotrophic factor (BDNF), anti-glial cell-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT3). Our results showed important protective effects of DMF in an animal model of SCI, considerably improving recovery of motor function, possibly by reducing the secondary inflammation and tissue injury that characterize this model. DMF may constitute a promising target for future SCI therapies.

Topics: Animals; Fumarates; Male; Mice; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Recovery of Function; Spinal Cord Injuries

Positively charged oligo[poly(ethylene glycol) fumarate] (OPF+) scaffolds loaded with Schwann cells bridge spinal cord injury (SCI) lesions and support axonal regeneration in rat. The regeneration achieved is not sufficient for inducing functional recovery. Attempts to increase regeneration would benefit from understanding the effects of the scaffold and transplanted cells on lesion environment. We conducted morphometric and stereological analysis of lesions in rats implanted with OPF+ scaffolds with or without loaded Schwann cells 1, 2, 3, 4, and 8 weeks after thoracic spinal cord transection. No differences were found in collagen scarring, cyst formation, astrocyte reactivity, myelin debris, or chondroitin sulfate proteoglycan (CSPG) accumulation. However, when scaffold-implanted animals were compared with animals with transection injuries only, these barriers to regeneration were significantly reduced, accompanied by increased activated macrophages/microglia. This distinctive and regeneration permissive tissue reaction to scaffold implantation was independent of Schwann cell transplantation. Although the tissue reaction was beneficial in the short term, we observed a chronic fibrotic host response, resulting in scaffolds surrounded by collagen at 8 weeks. This study demonstrates that an appropriate biomaterial scaffold improves the environment for regeneration. Future targeting of the host fibrotic response may allow increased axonal regeneration and functional recovery.

Topics: Animals; Astrocytes; Calcium-Binding Proteins; Female; Fumarates; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Macrophages; Microfilament Proteins; Microglia; Myelin Basic Protein; Phenotype; Polyethylene Glycols; Prosthesis Implantation; Proteoglycans; Rats, Sprague-Dawley; Schwann Cells; Spinal Cord Injuries; Time Factors; Tissue Scaffolds

This study describes the use of oligo [(polyethylene glycol) fumarate] (OPF) hydrogel scaffolds as vehicles for sustained delivery of dibutyryl cyclic adenosine monophosphate (dbcAMP) to the transected spinal cord. dbcAMP was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres, which were embedded within the scaffolds architecture. Functionality of the released dbcAMP was assessed using neurite outgrowth assays in PC12 cells and by delivery to the transected spinal cord within OPF seven channel scaffolds, which had been loaded with Schwann cells or mesenchymal stem cells (MSCs). Our results showed that encapsulation of dbcAMP in microspheres lead to prolonged release and continued functionality in vitro. These microspheres were then successfully incorporated into OPF scaffolds and implanted in the transected thoracic spinal cord. Sustained delivery of dbcAMP inhibited axonal regeneration in the presence of Schwann cells but rescued MSC-induced inhibition of axonal regeneration. dbcAMP was also shown to reduce capillary formation in the presence of MSCs, which was coupled with significant functional improvements. Our findings demonstrate the feasibility of incorporating PLGA microsphere technology for spinal cord transection studies. It represents a novel sustained delivery mechanism within the transected spinal cord and provides a platform for potential delivery of other therapeutic agents.

Topics: Animals; Axons; Biocompatible Materials; Bucladesine; Delayed-Action Preparations; Fumarates; Guided Tissue Regeneration; Hydrogels; Lactic Acid; Microspheres; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries