A hydrogel engineered to deliver minocycline locally to the injured cervical spinal cord protects respiratory neural circuitry and preserves diaphragm function

NEUROBIOLOGY OF DISEASE

卷:127

Article

Ghosh, Biswarup¹  Nong, Jia²  Wang, Zhicheng²  Urban, Mark W.¹  Heinsinger, Nicolette M.¹  Trovillion, Victoria A.¹  Wright, Megan C.³  Lepore, Angelo C.¹  Zhong, Yinghui² 

[1] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Vickie & Jack Farber Inst Neurosci, Dept Neurosci, 233 S 10th St,Bluemle Life Sci Bldg,Room 245, Philadelphia, PA 19107 USA

[2] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, 3141 Chestnut St,Bossone 7-716, Philadelphia, PA 19104 USA

[3] Arcadia Univ, Dept Biol, 450 S Easton Rd,220 Boyer Hall, Glenside, PA 19038 USA

关键词: Cervical;    Spinal cord injury;    Contusion;    Phrenic motor neuron;    Diaphragm;    Respiratory;    Minocycline;    Biomaterials;    Hydrogel;    Drug delivery;   

DOI  :  10.1016/j.nbd.2019.04.014

来源: Elsevier

【 摘 要 】

We tested a biomaterial-based approach to preserve the critical phrenic motor circuitry that controls diaphragm function by locally delivering minocycline hydrochloride (MH) following cervical spinal cord injury (SCI). MH is a clinically-available antibiotic and anti-inflammatory drug that targets 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 that cannot be achieved by systemic administration, which limits its clinical efficacy. We have developed a hydrogel-based MH delivery system that can be injected into the intrathecal space for local delivery of high concentrations of MH, without damaging spinal cord tissue. Implantation of MH hydrogel after unilateral level-C4/5 contusion SCI robustly preserved diaphragm function, as assessed by in vivo recordings of compound muscle action potential (CMAP) and electromyography (EMG) amplitudes. MH hydrogel also decreased lesion size and degeneration of cervical motor neuron somata, demonstrating its central neuroprotective effects within the injured cervical spinal cord. Furthermore, MH hydrogel significantly preserved diaphragm innervation by the axons of phrenic motor neurons (PhMNs), as assessed by both detailed neuromuscular junction (NMJ) morphological analysis and retrograde PhMN labeling from the diaphragm using cholera toxin B (CTB). In conclusion, our findings demonstrate that local MH hydrogel delivery to the injured cervical spinal cord is effective in preserving respiratory function after SCI by protecting the important neural circuitry that controls diaphragm activation.

【 授权许可】

Free