Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice.
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of polyglutamine repeat within ataxin-1 protein. Cerebellar Purkinje cells are the primary targets of SCA1 pathology. These cells synthesize insulin-like growth factor-I (IGF-I) and express its receptors during their entire life. The aim of present study was to determine if intranasally administered IGF-I to SCA1 transgenic mice suppresses toxic effects of ataxin-1. Two-week old SCA1 heterozygous animals were randomly divided into two treatment groups of IGF-I (30 and 60 microg IGF-I/animal) and a vehicle-treated control group. The wildtype animals served as normal controls. IGF-I or vehicle was administered at 48 h intervals for the total of 10 doses. Animals were then subjected to rotarod test, sacrificed, brains removed and processed for immunohistochemical and Western blot analysis. Radiolabeled IGF-I and bioactive TAT peptide accumulated in the brains of SCA1 mice following intranasal administration validating the use of intranasal route. SCA1 mice showed SCA1 pathology with impaired motor function and downregulation of calcium binding proteins as compared to wildtype mice. However, 30 and 60 microg IGF-I-treated animals showed improved performance on the rotarod as compared to vehicle-treated SCA1 mice with significant improvement (p < 0.05) on day 3 in 60 microg IGF-I group. The immunohistochemical data further showed partial recovery in the expression of calbindin D28k and protein kinase C-gamma in Purkinje cells in IGF-I-treated SCA1 animals. Our results indicate that suppression of ataxin-1-mediated adverse effects by intranasal IGF-I treatment may be of a therapeutic value to treat SCA1.
Vig
P J S
PJ
Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA. pvig@neurology.umsmed.edu
Subramony
S H
SH
D'Souza
D R
DR
Wei
J
J
Lopez
M E
ME
D000281:Administration, Intranasal; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015696:Gene Products, tat / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects* / Q000473:pathology*; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054322:tat Gene Products, Human Immunodeficiency Virus
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015696:Gene Products, tat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C415751:tat peptide (1-9), Human immunodeficiency virus 1; D007334:Insulin-Like Growth Factor I