Heparan sulfate mediates neuroprotection from degeneration in experimental glutaric aciduria.
Journal - Cell transplantation (United States )
Glutaric aciduria type 1 (GA1) is a childhood metabolic disorder associated with crises that lead to striatal necrosis. Although the disorder can be controlled with diet, there is no current treatment to ameliorate the neurodegeneration following a metabolic crisis. We hypothesized that heparan sulfate (HS) administration would stimulate neural stem cell proliferation by dimerizing with FGF-2 and binding to the FGF-2 receptor on neural stem cells, thus enhancing the number of newly generated neurons to repair damage following a metabolic crisis. In addition, FGF-2 is known to exert neuroprotective effects independent of neurogenesis, so HS may also have neuroprotective activities. To test these hypotheses, ibotenic acid was injected into the striatum of adult mice, mimicking the metabolic crisis and damage caused by glutaric aciduria. Daily doses of HS and bromodeoxyuridine (BrdU) or BrdU alone were administered starting 1 day after the ibotenic acid lesion. BrdU was used to label dividing cells. Fluorescent immunohistochemistry was used to quantify the lesion size and evaluate the phenotype of BrdU-positive cells. Intrastriatal administration of ibotenic acid resulted in a substantial striatal lesion that occupied 18.5% of the ipsilateral brain hemisphere. In contrast, animals treated with HS exhibited a lesion volume representing <1% of the ipsilateral brain hemisphere (ANOVA; p < 0.0001). Increased neurogenesis, however, was not observed in this group. These results suggest that HS administration 2 days after a "metabolic crisis" can ameliorate brain injury in an animal model of GA1. The neuroprotective mechanisms of HS, however, remain to be elucidated but may exert their actions indirectly through binding with FGF-2.
|ISSN : ||0963-6897|
|Mesh Heading : ||Amino Acid Metabolism, Inborn Errors Animals Antimetabolites Brain Bromodeoxyuridine Child Disease Models, Animal Excitatory Amino Acid Agonists Female Glutarates Heparitin Sulfate Humans Ibotenic Acid Mice Neuroprotective Agents genetics metabolism therapeutic use cytology drug effects pathology therapeutic use toxicity metabolism toxicity metabolism|
|Mesh Heading Relevant : ||drug therapy urine therapeutic use therapeutic use|