Local delivery of minocycline from metal ion-assisted self-assembled complexes promotes neuroprotection and functional recovery after spinal cord injury

Abstract

Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations. The inability to translate the high doses of MH used in experimental animals to tolerable doses in human patients limits its clinical efficacy. In addition, the duration of MH treatment is limited because long-term systemic administration of high doses of MH has been shown to cause liver toxicity and even death. We have developed a drug delivery system in the form of hydrogel loaded with polysaccharide-MH complexes self-assembled by metal ions for controlled release of MH. This drug delivery system can be injected into the intrathecal space for local delivery of MH with sufficient dose and duration, without causing any additional tissue damage. We show that local delivery of MH at a dose that is lower than the standard human dose (3 mg/kg) was more effective in reducing secondary injury and promoting locomotor functional recovery than systemic injection of MH with the highest dose and duration reported in experimental animal SCI (90–135 mg/kg).

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

“…As such, inhibition of RGMa/Neogenin shows promise in improving clinical outcomes for SCI. In fact, AbbVie Inc. has developed the human anti-RGMa antibody (Lee et al, 2003;Wells et al, 2003;Stirling et al, 2004;Festoff et al, 2006;Wang Z. et al, 2017), and a Phase II clinical trial suggested that there may be improvement after acute SCI (Casha et al, 2012). There is an ongoing Phase III clinical trial (NCT01828203) that was expected to complete in June of 2018, but no results have been posted.…”

Dual regulation of microglia and neurons by Astragaloside IV‐mediated mTORC1 suppression promotes functional recovery after acute spinal cord injury

“…Nowadays, local delivery of drug with sustained release ability has become a new trend for SCI therapy. [55][56][57][58] Thus, further studies are needed to find a more suitable delivery system for AS-IV.…”

Effects of Cyclosporin-A, Minocycline, and Tacrolimus (FK506) on Enhanced Behavioral and Biochemical Recovery from Spinal Cord Injury in Rats

“…Minocycline, a semisynthetic second-generation tetracycline, has robust neuroprotective effects in rodent models of neurodegenerative diseases [26] and provides Effects of Cyclosporin-A, Minocycline, and Tacrolimus (FK506) on Enhanced Behavioral… DOI: http://dx.doi.org /10.5772/intechopen.85212 neuroprotection in experimental models of neurological diseases, including SCI [27]. In a broad range of secondary injury mechanisms via its anti-inflammatory, antioxidant, and antiapoptotic properties, minocycline is effective in reducing secondary injury and promoting locomotor functional recovery [28][29][30][31]. Minocycline prevents N-methyl-d-aspartate (NMDA)-induced excitotoxicity by diminishing NMDA-induced Ca 2+ influx and mitochondrial Ca 2+ uptake [32] and protects gray and white matter from SCI [33].…”

“…In a murine model of SCI, minocycline treatment was superior to methylprednisolone in promoting functional improvement [44] and had neuroprotective effects on the SCI epicenter [47], motor neuron recovery, and neuropathic pain [48]. Minocycline has recently been reported to be effective in reducing secondary injury and promoting locomotor functional recovery in experimental SCI [28].…”