Table 1.
RGMa-related possible mechanisms involved in CNS diseases.
| Disease | Expression site of RGMa | Possible mechanisms | Participants or models | Potential therapeutic target |
|---|---|---|---|---|
| MS | (1) Significantly upregulated in active and chronic MS lesions [22, 61] (2) Plasma RGMa is inversely related to delta EDSS [2, 6] |
(1) Mediates immune responses [5, 37, 61–64] (2) Mediates CNS demyelination [38, 39] (3) Mediates neurodegeneration and inhibits neurite outgrowth [5, 7, 22, 40] (4) Inhibits neovascularization [5, 36, 65] (5) May be involved in BBB dysfunction [43–45, 66] |
(1) MS patients [6, 22, 44] (2) EAE rats [5, 61] |
(1) Targeting RGMa can improve functional recovery [22] (2) Anti-RGMa antibody can promote neurite outgrowth and remyelination [5, 22] (3) Anti-RGMa antibody can reduce immune responses [5] |
| NMOSD | Unknown | (1) May involve loss of AQP4, GFAP, and astrocytes [8, 46, 67] (2) May aggravate immune responses [8, 47, 68, 69] (3) May induce neuronal damage [8, 48, 49] |
NMOSD model in rats [8] | Inhibition of RGMa can (1) delay onset [8] (2) relieve symptoms [8] (3) delay progression of NMOSD [8] |
| Ischemic stroke | Upregulated in vascular endothelium and neurons after I/R injury [9, 36] | (1) Inhibits axon growth by phosphorylating CRMP-2 [51] (2) Might inhibit angiogenesis by downregulating BDNF VEGF, Ang1, and Ang2 [35] (3) May reduce p-FAK (Tyr397) and VEGF via Neogenin and Unc5b [34] (4) Might impact LMC status [53] (5) May be involved in BBB dysfunction via the CDC-42/PAK-1 signal pathway [9] |
(1) MCAO patients [53] (2) I/R injury model in rats [9, 35] (3) Endothelial cell in vitro [34] |
(1) Anti-RGMa antibody or RGMa function-blocking peptide can significantly upregulate BDNF, VEGF, Ang1, and Ang2 [34, 35] (2) Inhibition of RGMa promotes functional recovery by promoting angiogenesis [35] (2) RGMa may predict LMC status [53] (3) Silencing RGMa ameliorates infarct volume, brain edema, and BBB dysfunction [9] |
| SCI | Upregulated around SCI lesion [30, 70] | (1) Inhibits neuronal survival [30] (2) Activates microglia [21] |
(1) Patients with SCI [21] (2) SCI model in monkey [10, 71] (3) SCI model in mice [30, 72] |
(1) Anti-RGMa antibody can promote axon regeneration, plasticity, motor recovery, and manual dexterity [10, 21, 30, 72] (2) Anti-RGMa antibody can relieve neuralgia [21] |
| PD | Significantly upregulated in the SN of patients with PD [11, 73] | (1) Induces selective degeneration of dopaminergic neurons in the SN [11, 74] (2) Activates microglia and astrocyte strongly [11, 74] (3) May inhibit neuronal survival by activating RhoA [58, 74] |
(1) Patients with PD [11, 73] (2) RGMa can model PD in mouse [11] |
(1) Inhibition of RGMa may modify PD [11, 75] (2) Regulating RGMa-Neogenin may promote cell replacement [74] (3) Anti-RGMa antibody may offer neuroprotection [74] |
| Seizures | Significantly decreased in epileptic patients and rat models [12, 58, 76] | (1) Partly via the FAK-p120Ras GAP-Ras signaling pathway suppresses MFS [12, 76] (3) Inhibits hyperexcitability of hippocampal neurons via suppressing NMDAR-mediated currents [58] |
(1) Epileptic patients [58] (2) Pentylenetetrazol rat model [12] (3) Epileptic rat model [58] (4) Organotypic slice model [58] |
Injection recombinant RGMa to intracerebroventricular or overexpression of RGMa suppresses MFS and seizures [12, 58, 76] |
RGMa: repulsive guidance molecule-a; EAE: experimental autoimmune encephalomyelitis; NMOSD: neuromyelitis optica spectrum disorders; AQP4: aquaporin-4; MCAO: middle cerebral artery occlusion; I/R: ischemia-reperfusion; CRMP-2: collapsin response mediator protein 2; LMCs: leptomeningeal collaterals; SCI: spinal cord injury; PD: Parkinson's disease; SN: substantia nigra; PTZ: pentylenetetrazol; MFS: mossy fiber sprouting.