Table 2 Summary of potential BSCB treatment strategies for degenerative cervical myelopathy
From: Blood-spinal cord barrier disruption in degenerative cervical myelopathy
Category | Treatment | Mechanism | Evidence of BBB/BSCB support |
|---|---|---|---|
Cell therapy | Mesenchymal stem cell (MSC) transplantation | Paracrine trophic support, immunomodulation, engraftment into BSCB, and angiogenesis [142] | AD-MSCs engraft into blood vessels to promote angiogenesis and recruit pericytes in SCI rats [149] UC-MSCs and BM-MSCs engraft into vascular wall, preserve BBB, and support angiogenesis in ischemic stroke (IS) mice [235,236,237,238] BM-MSCs reduce EB extravasation and increase filament density in astrocytes in LPS-treated rats [239] AD-MSCs alleviate brain edema in intracerebral hemorrhage (ICH) mice [240] |
Neural stem cell (NSC) transplantation | F-NSCs associate with cerebral vasculature, decrease MMP9 expression, decrease IgG and biotin extravasation, and preserve TJs in IS mice [141, 241] aSVZ-NSCs robustly become VLA-1 + pericytes and modulate CNS inflammation and leukocyte trafficking in MS mice [151] hESC-NSCs and F-NSCs predominately become pericytes in a mouse model of PD [152] | ||
Cell-derived exosomes | Release of trophic factors and miRNA that preserve and stimulate growth of cells of the BSCB, modulate inflammation, and facilitate angiogenesis, leading to BSCB support [242,243,244,245] | Mouse Mouse pericyte-derived exosomes reduce lesion size, ameliorate microcirculation, reduce EB extravasation, preserve TJs, and reduce edema in SCI mice [242] Human BM-MSCs-derived exosomes enhance neurorestoration in a porcine model of TBI by reducing brain swelling, decreasing intracranial pressure, and supporting BBB integrity evidenced by decreased albumin extravasation and increased TJ expression [246] Rat BM-MSCs-derived exosomes increase TJ expression, promote remyelination, and decrease MMP-9 in IS mice [156] | |
Gene therapy | AAV-delivery of growth factors | Expression of growth factors by BSCB cells, angiogenesis, and neuronal sprouting | AAV-delivery of FGF, EGF, and GDNF revascularizes glial scar and forms neurite growth-supportive environment [177] |
ChABC | Vascular and astrocytic remodelling | ChABC attenuates hypertrophy of blood vessels and basement membrane pathology while facilitating vascular remodelling [178] | |
siRNA | Inhibition of proinflammatory cascades | siRNA-mediated inhibition of P2X purinergic receptor and Tim-3 attenuate neuroinflammation and edema in ICH mice and reduce neuropathic pain in rats [183,184,185,186] | |
Growth factors & mitogenic agents | Fibroblast growth factors (bFGF) | Reduction of autophagy and ER stress, maturation of BSCB, and proliferation of endogenous NSCs [159] | bFGF improves functional recovery in SCI rats via attenuation of autophagy and BSCB reconstitution evidenced by decrease in EB and dextran extravasation, inhibition of MMP9, and preservation of TJs [161,162,163,164] bFGF enhances proliferation and maturation of NSCs and protects the BBB by upregulating TJs in  traumatic brain injury (TBI) rats [165, 166] |
Platelet derived-growth factor BB (PDGF-BB) | Increase pericyte coverage, reduce pathological activation of pericytes, and maturation of the BSCB [157, 158] | Intrathecal delivery of PDGF-BB in PD mice increases pericyte coverage in the dorsolateral striatum and reduces pathological activation of pericytes, leading to behavioral recovery [167] Intraspinal delivery of PDGF-BB in SCI mice increases TJ expression, reduces autophagy, increases revascularization, and reduces EB extravasation, leading to improvement in recovery [168] | |
Epidermal growth factor (EGF) | Proliferation and migration of NSCs, protection of BSCB from oxidative stress, maturation of the BSCB | EGF reduces EB extravasation and preserves TJs via PI3K pathway, induces migration of ependymal cells and astrocytes to the injured spinal cord, and decreases oxidative stress and apoptosis, leading to improved functional recovery in SCI rats [169,170,171] | |
Adropin | Proliferation and maturation of endothelial cells [160] | Adropin decreased endothelial cell monolayer permeability to dextran and decreased macrophage infiltration in vitro via NO release [172] In ICH mice, intraperitoneal adropin led to decreased hematoma, brain edema, and EB and IgG extravasation, leading to improvement in behavioral outcomes via Notch1 signaling [173, 247] | |
Molecular inhibitors & antibodies | Anti-Nogo-A | Neutralization of Nogo-A, a membrane protein expressed by oligodendrocytes and neurons that inhibit neurite outgrowth and angiogenesis [187,188,189] | Expression of TJ and BBB permeability is restored in anti-Nogo-A treated IS mice, especially upon co-administration of VEGF, leading to improved revascularization of the peri-infarct cortex [192] |
Imatinib | Inhibition of PDGF-CC signaling [248] | Intraperitoneal injection of imatinib preserves BBB integrity in ICH mice, evidenced by decreased brain edema, EB extravasation, and MMP-9 activity [249] In MS mice, oral imatinib led to decreased dextran extravasation and immune cell trafficking [250] Oral imatinib inhibits oxidative stress response and modulates neuroinflammation, leading to BSCB support in SCI rats, shown by preservation of TJs, reduced IgG and albumin extravasation, and prevention of pericyte detachment from the blood vessel wall [193, 194] | |
4-Phenylbutyric acid (PBA) | Attenuation of ER stress by acting as chemical chaperone [195] | PBA treatment leads to reduced EB extravasation, increased pericyte coverage, and preservation of TJ and microvessels in SCI rats via modulating expression of ER stress markers [195, 196, 251] | |
Salubrinal | Deactivation of ER stress pathway via inhibition of PP1α phosphatase [252] | Salubrinal treatment for a mouse model of TBI increases PDGF-BB expression in neurons while decreasing microglia activation and EB extravasation [197] In SCI rats, Salubrinal protects neurons and oligodendrocytes from apoptosis, leading to functional recovery [198] | |
Immune modulators | Infliximab | Inhibition of TNF-α | Infliximab significantly ameliorates endothelial necroptosis and BBB disruption, as shown by MRI-imaging and decreased EB extravasation in IS mice [202] |
Calpastatin | Inhibition of calpain (calcium-dependent proteolytic system) [253] | Calpastatin decreases caspase-mediated cell apoptosis in SAH mice, leading to reduced EB extravasation and decreased brain edema volume [204] | |
Shikonin | Attenuation of NK-κB signaling and ER stress | Shikonin reduces spinal cord edema and prevents apoptosis in SCI rats, leading to increased motor recovery [205] | |
Curcumin | Attenuation of TNF-α signaling [254] | Curcumin reduces EB extravasation and increases TJ expression via attenuation of TNF-α signaling, promoting motor recovery in SCI rats [207] | |
Salvianolic Acid B | Attenuation of TNF-α signaling and oxidative stress [255] | Salvianolic acid leads to decrease in spinal cord edema, EB extravasation, and preservation of TJs, due to attenuation of oxidative stress and inflammation in SCI rats and rat spinal cord ischemia–reperfusion induced neuronal injury [208, 256] | |
Alternative therapies | Vitamin B12, B6, Folate | Metabolism of neurotoxic homocysteine associated with BBB breakdown [217, 257] | Enhanced amyloid clearance and pericyte rescue in Alzheimer's disease (AD) mouse model [257] Improved serum/CSF ratio of albumin and cognitive function in hyperhomocysteinemia patients with mild cognitive impairment [217] |
Omega-3 Fatty Acids | Reduction of inflammation-induced MMP-9 and -6 activity and BBB hyperpermeability [219] | Decreased extravasation of serum tracers and preservation of TJs in ischemic brain injury, AD, and post-operative delirium mouse models [258,259,260] High serum omega-3 levels correlate with improved BBB determined by contrast-enhanced MRI [220] | |
Gut therapy | Prevention of systemic infiltration of neurotoxin bacteria and metabolites [225]. Promotion of SCFAs production [226] | Probiotic and micro-derived methylamines led to restored TJs and BBB integrity to EB in aged and stressed mice [227, 228, 230] | |
Photobiomodulation | Maturation of BSCB cells and pericyte mobilization [232,233,234] | Decreased edema and serum extravasation in IS mice [234] Preservation of retinal capillaries and decreased extravasation in diabetic mice [261] Increased cerebral perfusion in Alzheimer’s Disease patients [262] |