Inhibition of CSPG receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke

Luo, Fucheng; Wang, Jiapeng; Zhang, Zhen; You, Zhen; Bedolla, Alicia; Okwubido-Williams, FearGod V; Huang, Lulu; Silver, Jerry; Luo, Yu

doi:10.1016/j.celrep.2022.111137

Cited by 25 publications

(20 citation statements)

References 97 publications

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“…These results suggest that EA treatment enhanced CST axon regeneration after stroke; this may be related to EA stimulation and amplification of endogenous recovery mechanisms after brain injury and promotion of brain remodeling. Axonal regeneration, as an important mechanism for restoring neurological function after ischemic brain injury, is becoming a rapidly developing field [39]. In other studies, catalpol has been shown to activate mTOR and its downstream S6 protein, thereby inducing cellular activity and ultimately activating axonal regeneration after stroke [31].…”

Section: Discussionmentioning

confidence: 99%

“…Axonal regeneration, as an important mechanism for restoring neurological function after ischemic brain injury, is becoming a rapidly developing field [ 39 ]. In other studies, catalpol has been shown to activate mTOR and its downstream S6 protein, thereby inducing cellular activity and ultimately activating axonal regeneration after stroke [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Electroacupuncture Activates Neuroplasticity in the Motor Cortex and Corticospinal Tract via the mTOR Pathway in a Rat P-MCAO Model

Zhang

Yin

Jin

et al. 2022

BioMed Research International

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Electroacupuncture (EA) combines traditional Chinese medicine acupuncture theory with modern scientific technology. It is a promising therapy for the treatment of cerebrovascular diseases such as cerebral infarction. A large number of clinical studies have shown that EA promotes recovery of neurological function after cerebral infarction, however, the underlying mechanisms behind its effects remain unclear. We tested whether EA stimulation of the Zusanli (ST36) and Neiguan (PC6) acupoints activates neuroplasticity in rats with ischemic stroke and whether this involves the regulation of axonal regeneration through the mTOR pathway. 24 h after permanent middle cerebral artery occlusion (p-MCAO) in rats, EA treatment was started for 20 min, daily, for 14 days. We found that EA significantly reduced Modified Neurological Severity Scores (mNSS), cerebral infarct volume, and apoptosis of neuronal cells. EA also significantly increased the expression of the neuroplasticity-associated proteins GAP-43 and SYN and upregulated the phosphorylation levels of AKT, mTOR, S6, and PTEN to promote CST axon sprouting in the spinal cord at C1–C4 levels. The positive effects of EA were blocked by the administration of the mTOR inhibitor Rapamycin. In short, we found that EA of the Zusanli (ST36) and Neiguan (PC6) acupoints in p-MCAO rats induced neuroprotective and neuroplastic effects by regulating the mTOR signaling pathway. It promoted neuroplasticity activated by axon regeneration in the contralateral cortex and corticospinal tract. Activation of such endogenous remodeling is conducive to neurological recovery and may help explain the positive clinical effects seen in patients with infarcts.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Electroacupuncture Activates Neuroplasticity in the Motor Cortex and Corticospinal Tract via the mTOR Pathway in a Rat P-MCAO Model

Zhang

Yin

Jin

et al. 2022

BioMed Research International

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“…It has been shown that CSPGs are the most important component of the glial scar that hinders regeneration after CNS injury, and their combination alone or with other extracellular matrix causes axonal extension toward the site of injury to stop at the glial scar, and that CSPGs reduce the plasticity of axonal growth (125). CSPG acts as an axon growth inhibitor by binding to PTPσ receptors to activate the downstream Rho A/ROCK pathway (12). Another study found that after nerve injury, the regeneration of injured axons and partial recovery of function was effectively promoted by eliminating CSPGs in the brain and spinal cord (125,126).…”

Section: Figurementioning

confidence: 99%

“…The compensatory repair capacity of the brain for ischemic injury is limited and a favorable microenvironment is needed (11). After a stroke, the reconstruction of neural circuits is restricted by the presence of many inhibitory factors that inhibit neurogenesis in the local microenvironment, the lack of growth factors, as well as the formation of glial scars in the injured area (12). An enriched microenvironment exerts a significant influence on neurogenesis (13,14).…”

Section: Introductionmentioning

confidence: 99%

The factors affecting neurogenesis after stroke and the role of acupuncture

Ma²,

Zhang³

et al. 2023

Front. Neurol.

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Stroke induces a state of neuroplasticity in the central nervous system, which can lead to neurogenesis phenomena such as axonal growth and synapse formation, thus affecting stroke outcomes. The brain has a limited ability to repair ischemic damage and requires a favorable microenvironment. Acupuncture is considered a feasible and effective neural regulation strategy to improve functional recovery following stroke via the benign modulation of neuroplasticity. Therefore, we summarized the current research progress on the key factors and signaling pathways affecting neurogenesis, and we also briefly reviewed the research progress of acupuncture to improve functional recovery after stroke by promoting neurogenesis. This study aims to provide new therapeutic perspectives and strategies for the recovery of motor function after stroke based on neurogenesis.

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“…Thus, inhibitory CSPGs up-regulate expansively along the neuraxis within, proximal and distal to the lesion epicenter, leading to limited regeneration through the lesion or back into target nuclei and curtailing potential sprouting/plasticity over large distances that could occur from remaining or spared fiber systems either ipsilateral or contralateral to the lesion [10][11][12][13][14][15][16]19,20,75 . The regulatory effects of CSPGs on both myelin and axon regeneration as well as neuronal plasticity after an acute 9,[21][22][23][24][25][26] or sub-chronic 5,17,21,24 SCI, and in the context of many other conditions 8,12,84 have been well documented.…”

Section: Introductionmentioning

confidence: 99%

Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ

Milton

Silver

Kwok

et al. 2022

Preprint

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Spinal cord injuries, for which there are limited effective clinical treatments, result in enduring paralysis and hypoesthesia due, in part, to the inhibitory microenvironment that develops and limits regeneration/sprouting, especially during chronic stages. Recently, we discovered that targeted enzymatic modulation of the potently inhibitory chondroitin sulfate proteoglycan (CSPG) component of the extracellular and perineuronal net (PNN) matrix via Chondroitinase ABC (ChABC) can rapidly restore 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 rapid, albeit modest, improvements in upper arm function. In the present study, we sought to further optimize and elucidate the capacity for nerve sprouting and/or regeneration to restore gross 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, non-invasive combinatorial treatment strategy designed to both reduce (via oral delivery of 4-methylumbelliferone) and overcome inhibitory CSPGs (via sub-cutaneous delivery of the PTPσ CSPG receptor blocking peptide ISP) simultaneously and spatially extensively. Following a three-month upper cervical spinal hemi-lesion, we show that the combined treatment has a profound effect on functional recovery of the chronically paralyzed forelimb and paw, specifically during walking as well as precision movements of the digits. Our exciting pre-clinical findings will begin to dramatically enhance our understanding of the basic mechanisms underlying functionally beneficial regenerative events occurring at chronic injury stages for clinically relevant translational benefits.

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Inhibition of CSPG receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke

Cited by 25 publications

References 97 publications

Electroacupuncture Activates Neuroplasticity in the Motor Cortex and Corticospinal Tract via the mTOR Pathway in a Rat P-MCAO Model

Electroacupuncture Activates Neuroplasticity in the Motor Cortex and Corticospinal Tract via the mTOR Pathway in a Rat P-MCAO Model

The factors affecting neurogenesis after stroke and the role of acupuncture

Recovery of forearm and fine digit function after chronic spinal cord injury by simultaneous blockade of inhibitory matrix CSPG production and the receptor PTPσ

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