A Select Combination of Neurotrophins Enhances Neuroprotection and Functional Recovery following Spinal Cord Injury

Abstract

Previously, we have shown that topical application of brain-derived neurotrophic factor (BDNF) or insulin-like growth factor 1 (IGF-1) given within 5 to 30 min after a focal trauma to the rat spinal cord attenuates spinal cord injury (SCI)-induced breakdown of the blood-spinal cord barrier (BSCB), edema formation, motor dysfunction, and cell injury. This investigation was undertaken to find out whether a combination of select neurotrophins (BDNF, glial cell line-derived neurotrophic factor [GDNF], neurotrophin 3 [NT-3], or nerve growth factor [NGF]) will further enhance the neuroprotective efficacy of growth factors in SCI. The neurotrophins (0.1-1 microg/10 microL in phosphate-buffered saline) were applied 30, 60, or 90 min after injury topically over the traumatized spinal cord either alone or in combination. The SCI was performed by making a unilateral incision into the right dorsal horn of the T10-T11 segment under Equithesin anesthesia. The rats were allowed to survive 5 h after trauma. Topical application of BDNF, GDNF, or NGF 30 min after SCI in high concentration (0.5 microg and 1 microg) significantly improved the motor functions and reduced the BSCB breakdown, edema formation, and cell injury seen at 5 h. These beneficial effects of neurotropins were absent when administered separately either 60 or 90 min after SCI. However, a combination of BDNF and GDNF (but not with NT-3 or NGF) given either 60 or 90 min after SCI significantly reduced the motor dysfunction and spinal cord pathology at 5 h. These novel observations suggest that a select group of neurotrophins in combination have potential therapeutic value for the treatment of SCI in clinical situations.

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

“…This beneficial effect of Cerebrolysin may result from a combined action of multiple neurotrophic factors, such as CNTF, IGF-1, and GDNF. 8,55 Upregulation of MMP-9 contributes to the BBB damage and synaptic loss after experimental TBI. 16,27 Clinical studies show that MMPs may promote BBB opening and hemorrhage secondary to brain injury in patients.…”

“…35,55 Cerebrolysin is a mixture of low-molecular-weight neuropeptides derived from purified brain proteins by standardized enzymatic proteolysis, with proposed neuroprotective and neurotrophic properties similar to naturally occurring growth and neurotrophic factors. 48 For example, BDNF not only stimulates axonal sprouting 30 but also enhances the proliferation and differentiation of neural progenitor cells in the DG of the hippocampus after focal stroke, 64 which may contribute to the functional recovery.…”

Low-level laser therapy for spinal cord injury in rats: effects of polarization

“…Thus, SCI patients are left with serious residual disabilities, such as paralysis, respiratory difficulty, chronic pain, urinary problems, and neurologic decline, leading to considerable decrease in quality of life. Various strategies have been examined for repair of SCI in animal models, including blockage of the endogenous growth inhibitory factors, 1,2 infusion of neurotrophic factors, 3,4 and transplantation of growth promoting cells. [5][6][7] However, no effective treatment for SCI has yet been established.…”

Mesenchymal Stem Cell Therapy for Apoptosis After Spinal Cord Injury

“…Apoptosis induced by TNF-α after SCI could be mediated in part by nitric oxide via upregulation of inducible nitric oxide synthase (iNOS) (Yune et al, 2003). Although, few studies indicate a neuroprotective role of TNF-α and NOS expression in SCI, several investigators support a neurodestructive role of these agents in spinal cord pathology (Bethea et al, 1999;Bethea and Dietrich, 2002;Dolga et al, 2008;Gonz'alez Deniselle et al, 2001;Sharma et al, 1995;Sharma, 2007;Sharma, 2008;Sharma, 2010;Stalberg et al, 1998). Apoptosis of oligodendrocytes in vivo was shown to be induced by the overexpression of TNFR1 (Akassoglou et al, 1998).…”