A zebrafish assay for identifying neuroprotectants in vivo.
In this study, we developed an in vivo method to determine drug effects on oxidation-induced apoptosis in the zebrafish brain caused by treatment with L-hydroxyglutaric acid (LGA). We confirmed that LGA-induced apoptosis was caused by oxidation by examining the presence of an oxidative product, nitrotyrosine. Next, we examined the effects of 14 characterized neuroprotectants on LGA-treated zebrafish, including: D-methionine (D-Met), Indole-3-carbinol, deferoxamine (DFO), dihydroxybenzoate (DHB), deprenyl, L-NAME (N(G)-nitro-L-arginine methyl ester), n-acetyl L-cysteine (L-NAC), 2-oxothiazolidine-4-carboxylate (OTC), lipoic acid, minocycline, isatin, cortisone, ascorbic acid and alpha-tocopherol. Eleven of 14 neuroprotectants and 7 of 7 synthetic anti-oxidants exhibit significant protection in zebrafish. Buthionine sulfoximine (BSO), used as a negative control, exhibited no significant protective effects. In addition, three blood-brain barrier (BBB) impermeable compounds exhibited no significant effects. Our results in zebrafish were similar to results reported in mammals supporting the utility of this in vivo method for identifying potential neuroprotective anti-oxidants.
Parng
Chuenlei
C
Phylonix Pharmaceuticals, Inc., 100 Inman Street, Cambridge, MA 02139, USA. Chuenlei@phylonix.com
Ton
Christopher
C
Lin
Ying-Xin
YX
Roy
Nicole Marie
NM
McGrath
Patricia
P
D000166:Acridines / Q000633:toxicity; D000818:Animals; D000906:Antibodies; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005977:Glutarates / Q000494:pharmacology; D007090:Image Interpretation, Computer-Assisted; D008856:Microscopy, Fluorescence; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000276:immunology; D015027:Zebrafish / Q000502:physiology*
D000166:Acridines; D000906:Antibodies; D000975:Antioxidants; D015415:Biomarkers; D005977:Glutarates; D018696:Neuroprotective Agents; C403604:acridinium I; C019417:alpha-hydroxyglutarate; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine