Inhibition of glial proliferation, promotion of axonal growth and myelin production by synthetic glycolipid: A new approach for spinal cord injury treatment.
OBJECTIVE
After spinal cord injury (SCI) a glial scar is generated in the area affected that forms a barrier for axon growth and myelination, preventing functional recovery. Recently, we have described a synthetic glycolipid (IG20) that inhibited proliferation of human glioma cells. We show now that IG20 inhibited the proliferation of astrocytes and microglial cells, the principal cellular components of the glial scar, and promoting axonal outgrowth and myelin production in vitro.


METHODS
Glial cells were inhibited with IG20 (IC50≈10 μM) and studied by RT-PCR, Western Blotting, immunoprecipitation and fluorescence microscopy. Axonal outgrowth in dorsal root ganglia (DRG) and myelin production by oligodendrocytes were analyzed by immunocytochemistry. Adult rats were assayed in spinal cord contusion model and the recovery of treated animals (n = 6) and controls (n = 6) was followed.


RESULTS
The IG20 was localized in the cytosol of glial cells, forming a complex with RhoGDIα, a regulator of RhoGTPases. Treatment of astroglial cultures with IG20 increase the expression of BDNF receptor genes (TrkBT1, TrkB Full). IG20 reduced the astroglial marker GFAP, while increasing production of myelin basic protein in oligodendrocytes and promoted axonal outgrowth from DRG neurons. Local injection of IG20, near a spinal cord contusion, promoted the recovery of lesioned animals analyzed by BBB test (P <  0.05).


CONCLUSIONS
We propose that inhibition of astrocytes and microglia by IG20 could be diminished the glial scar formation, inducing the re-growth and myelination of axons, these elements constitute a new approach for SCI therapy.
Grupo de Química Neuro-regenerativa, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Finca La Peraleda s/n, Toledo, Spain.
Isabel
I
García-Álvarez
Instituto de Química Orgánica General, CSIC, Juan de la Cierva, Madrid, Spain.
Alfonso
A
Fernández-Mayoralas
Grupo de Química Neuro-regenerativa, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Finca La Peraleda s/n, Toledo, Spain.
Sandra
S
Moreno-Lillo
Grupo de Química Neuro-regenerativa, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Finca La Peraleda s/n, Toledo, Spain.
María
M
Sánchez-Sierra
Instituto Cajal, CSIC, Avda. Doctor Arce, Madrid, Spain.
Manuel
M
Nieto-Sampedro
Grupo de Química Neuro-regenerativa, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha (SESCAM), Finca La Peraleda s/n, Toledo, Spain.
Ernesto
E
Doncel-Pérez
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002921:Cicatrix / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006017:Glycolipids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D006017:Glycolipids; C000609953:IG20 compound; D018696:Neuroprotective Agents
Astrocyte; cortical neuron; dorsal root ganglia; glial scar; microglia; myelin basic protein; spinal cord injury