Targeting proteoglycan receptor PTPσ restores sensory function after spinal cord dorsal root injury by activation of Erks/CREB signaling pathway

  • Neuropharmacology. 2019 Jan:144:208-218. doi: 10.1016/j.neuropharm.2018.10.035.
Min Yao  1 ,  Haitao Sun  2 ,  Qiuju Yuan  3 ,  Ning Li  4 ,  Heng Li  5 ,  Yinjuan Tang  6 ,  Gilberto Kk Leung  7 ,  Wutian Wu  8
Affiliations
  • 1. School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, 999077, China; Department of Surgery, The University of Hong Kong, Hong Kong SAR, 999077, China.
  • 2. School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, 999077, China; The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 3. School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 4. Department of Surgery, The University of Hong Kong, Hong Kong SAR, 999077, China.
  • 5. School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, 999077, China.
  • 6. Department of Basic Medicine Sciences, Xiangnan University, Chenzhou, 423000, Hunan Province, China.
  • 7. Department of Surgery, The University of Hong Kong, Hong Kong SAR, 999077, China; Guangdong-Hongkong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, 510632, China. Electronic address: [email protected].
  • 8. School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, 999077, China; Guangdong-Hongkong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, 510632, China; Re-Stem Biotechnology Co., Ltd, Suzhou, 215300, China. Electronic address: [email protected].
PMID: 30393073 DOI: 10.1016/j.neuropharm.2018.10.035
Abstract

Dorsal root injury commonly results in irreversible loss of sensory functions because of the limited intrinsic regenerative capacity of adult sensory axons and the growth-inhibitory environment at the dorsal root entry zone (DREZ) between the dorsal root and the spinal cord. Chondroitin sulfate proteoglycans (CSPGs) are the dominant suppressors of axonal regeneration, acting via neuronal receptors including protein tyrosine phosphatase-σ (PTPσ). ISP (Intracellular Sigma Peptide) is a small peptide mimetic of the PTPσ wedge region that has been developed to target PTPσ and relieve CSPG inhibition. Extracellular regulated kinases (Erks) and cAMP response element binding protein (CREB) are signaling molecules downstream of CSPGs and PTPσ; they are expressed in neurons and essential for axon growth. In this study, we observed that ISP administration could promote sensory function restoration in adult rats after dorsal spinal root crush injury. Our results show that systemic ISP administration would not only significantly increase sensory axon regeneration and functional recovery, but also activate ERK and CREB signaling pathway. Furthermore, ISP has also been verified to increase dorsal root ganglion axonal remyelination in vitro. These results suggest that modulation of PTPσ by ISP represents a promising therapeutic strategy for sensory neuronal injuries.

Keywords
Axon regeneration; Dorsal root crush; ISP; PTPσ; Sensory refunction.
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