Vaccination with a neural‐derived peptide plus administration of glutathione improves the performance of paraplegic rats

Abstract

After damage to the central nervous system (CNS) the body is protected by an adaptive immune response which is directed against myelin-associated proteins. Active immunization with nonpathogenic derivatives of CNS-associated peptides (DCAP) reduces the degeneration of neurons and promotes motor recovery after spinal cord injury (SCI) in rats. In order to improve even more the neurological outcome obtained with this therapy, either a combination of DCAP immunization plus glutathione monoethyl ester (GSHE) or a double DCAP immunization were performed. GSHE is a cell-permeant derivative of glutathione, a potent antioxidant agent that significantly inhibits lipid peroxidation after SCI. After a contusive or compressive SCI, the combination of GSHE + DCAP immunization, induced better motor recovery, a higher number of myelinated axons and better rubrospinal neuron survival than immunization alone. On the other hand, double-DCAP immunization counteracted the protective effect of DCAP therapy. Motor recovery and neuronal survival of double-immunized rats were similar to those observed in control animals (PBS-treated). Further studies revealed that double immunization was not encephalitogenic but inhibited the proliferative response of T-cells specific to the DCAP-immunized peptide. This clonal dysfunction was probably secondary to anergy. GSHE improves the protective effect induced by DCAP immunization while double immunization, reverts it.

Autoreactivity against myelin basic protein in patients with chronic paraplegia

“…According to the study reported by Beck et al [16], immune cells serve as a reparative factor in chronic stages of lesion since, the blockade of these, reduced motor recovery and myelination in the injured spinal cord. In acute SCI, the protective and restorative actions of immune cells have also been widely demonstrated [11,12,15]. The findings of the present manuscript confirm the presence of MBP-reactive elements which could be beneficial in promoting restorative processes in patients with chronic SCI.…”

“…This is what we observe in autoimmune diseases like MS where anti-MBP lymphocytes and antibodies participate in CNS damage, under these conditions, the uncontrolled autoreactive reaction causes tissue destruction and aggravates the neurological impairment of patients. On the other hand, the modulation of autoreactive responses has shown to improve morphological and functional outcomes in MS and acute neurodegenerative diseases such as traumatic brain injury (TBI) or SCI [13][14][15]. Accordingly, if the reaction is immediately modulated (by immunizing with neural-derived antigens), even in individuals with the aforementioned factors, the autoreactive response is capable of providing beneficial effects.…”

Immunization with Neural-Derived Peptides as a Potential Therapy in Neurodegenerative Diseases

“…Results suggested that Cop-1 significantly improved the neurological outcome of animals after stroke. Histolopathological assessment also demonstrated a decrease in infarct size and infarct volume in Cop-1-treated animals (Ibarra et al, 2007). The results of both studies do not necessarily elucidate the mechanisms through which NDPinduced PA exerts its protective effects in focal cerebral ischemia but they provide evidence of its neuroprotective, and even neuroregenerative, properties.…”

“…The antioxidant properties of GSH will cover the overproduction of ROS from the beginning of injury while it could also assist in inducing a better PA response. A previous work carried out in our laboratory, examined the effect of this combination and demonstrated that the addition of GSHE to NDP immunizations induced earlier and better motor recovery after SCI compared to immunizations alone (Martinon et al, 2007). This effect was observed in animals subjected to either a contusive or a compressive SCI.…”

“…The findings support the notion that the second immunization after SCI has a negative effect on PA. Rather than strengthening the protective effect, it eliminated it. This phenomenon was probably secondary to anergy since double immunization did not induce cell death (Martinon et al, 2007). According to the present data, the use of NDP and GSHE in SCI is a promising strategy.…”