Heparan sulfate mediates neuroprotection from degeneration in experimental glutaric aciduria.
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.
Naylor
Michelle C
MC
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
Negia
Mesfin
M
Noetzel
Meredith
M
Burns
Terry C
TC
Demorest
Zach L
ZL
Low
Walter C
WC
D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D001973:Bromodeoxyuridine / Q000627:therapeutic use; D002648:Child; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D005977:Glutarates / Q000652:urine*; D006497:Heparan Sulfate / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007051:Ibotenic Acid / Q000633:toxicity; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*
D000963:Antimetabolites; D001973:Bromodeoxyuridine; D018690:Excitatory Amino Acid Agonists; D005977:Glutarates; D006497:Heparan Sulfate; D007051:Ibotenic Acid; D018696:Neuroprotective Agents; C035736:glutaric acid