TY - JOUR
T1 - Recovery of Forearm and Fine Digit Function After Chronic Spinal Cord Injury by Simultaneous Blockade of Inhibitory Matrix Chondroitin Sulfate Proteoglycan Production and the Receptor PTPσ
AU - Milton, Adrianna
AU - Kwok, Jessica
AU - McClellan, Jacob
AU - Randall, Sabre
AU - Lathia, Justin
AU - Warren, Philippa
AU - Silver, Daniel
AU - Silver, Jerry
N1 - Funding Information:
Financial support was provided by Wings for Life, the Ohio Department of Higher Education Third Frontier Program, The Brumagin-Nelson Fund, The Griffin Family, The Timothy Brodigan Trust, The Kaneko Family Fund, and the NIH National Institute of Neurological Disorders and Stroke (NINDS) (grants 1R01NS101105 and 1R011NS113831). We gratefully acknowledge the support of the Government of Canada's New Frontiers in Research Fund (Mend the Gap), from grant NFRFT-2020-00238, the Czech Science Agency (grant 19-10365S to J.C.F.K.) and the Medical Research Council UK (project grant MR/S011110/1 to J.C.F.K. and P.M.W.).
Publisher Copyright:
© Adrianna J. Milton et al. 2023; Published by Mary Ann Liebert, Inc.
PY - 2023/11/30
Y1 - 2023/11/30
N2 - Spinal cord injuries (SCI), for which there are limited effective treatments, result in enduring paralysis and hypoesthesia, in part because of the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic removal of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restored robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we focused on arm and hand function, seeking to highlight and optimize crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to simultaneously reduce and overcome inhibitory CSPGs. Following a 3-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, as well as on precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG-mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time points following SCI, hopefully leading to clinically relevant translational benefits.
AB - Spinal cord injuries (SCI), for which there are limited effective treatments, result in enduring paralysis and hypoesthesia, in part because of the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic removal of the inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) rapidly restored robust respiratory function to the previously paralyzed hemi-diaphragm after remarkably long times post-injury (up to 1.5 years) following a cervical level 2 lateral hemi-transection. Importantly, ChABC treatment at cervical level 4 in this chronic model also elicited improvements in gross upper arm function. In the present study, we focused on arm and hand function, seeking to highlight and optimize crude as well as fine motor control of the forearm and digits at lengthy chronic stages post-injury. However, instead of using ChABC, we utilized a novel and more clinically relevant systemic combinatorial treatment strategy designed to simultaneously reduce and overcome inhibitory CSPGs. Following a 3-month upper cervical spinal hemi-lesion using adult female Sprague Dawley rats, we show that the combined treatment had a profound effect on functional recovery of the chronically paralyzed forelimb and paw, as well as on precision movements of the digits. The regenerative and immune system related events that we describe deepen our basic understanding of the crucial role of CSPG-mediated inhibition via the PTPσ receptor in constraining functional synaptic plasticity at lengthy time points following SCI, hopefully leading to clinically relevant translational benefits.
UR - http://www.scopus.com/inward/record.url?scp=85174636386&partnerID=8YFLogxK
U2 - 10.1089/neu.2023.0117
DO - 10.1089/neu.2023.0117
M3 - Article
SN - 0897-7151
VL - 40
SP - 2500
EP - 2521
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 23-24
ER -