Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice
Introduction
Several growth factors and their specific receptors are expressed in the central nervous system suggesting a role in regulation of cell growth and differentiation in the developing and mature brain. Insulin-like growth factor-I (IGF-I) and its receptors are abundant in cerebellum [1], [2], [3], [22], [29] Cerebellar Purkinje cells synthesize IGF-I and express IGF-I receptors during their entire life [3]. IGF-I serves as a promoting factor for Purkinje cell development, particularly postnatal survival and dendritic growth [9]. Further, in Purkinje cells IGF-I up-regulates the signaling pathways involving the phosphoinositide 3-kinase, mitogen-activated protein kinase, and p38 kinase [9]. An additional source of IGF-I for these cells is provided by climbing fiber afferents originating in the inferior olive nucleus. IGF-I from the inferior olive is necessary for motor learning processes probably involving Purkinje cell synaptic plasticity [3], [14], [22].
IGF-I and its related molecules are also involved in neurodegenerative processes in which IGF-I-containing pathways are compromised [8]. Our earlier studies have demonstrated that the process of cerebellar degeneration in human olivopontocerebellar atrophy and in lurcher mutant mouse is associated with altered IGF-I receptor binding and protein tyrosine phosphorylation [24]. Further, it has been shown that patients with late-onset cerebellar ataxias with degeneration in their IGF-I containing neuronal pathways also show significant changes in the peripheral IGF system [8], [21], [29]. Zhang et al. [29] demonstrated that apoptotic Purkinje cells in Purkinje cell degeneration mice contain significantly low levels of IGF-I mRNA suggesting the involvement of IGF-I pathways in the degenerative processes. Furthermore, our recent data on double mutant mice generated by mating SCA1 transgenics with IGF-1 overexpressing transgenic mice showed that the double mutants have improved motor coordination on the rotating rod with decreased Purkinje cell pathology (unpublished observations). Therefore, the present study was undertaken to determine if intranasally administered IGF-I has any beneficial effects on the pathogenesis of SCA1 in SCA1 transgenic mice.
Section snippets
SCA-1 transgenic mice
The SCA-1 transgenic mice were generously provided by Drs. Harry Orr and Huda Zoghbi [5] at the University of Minnesota. The heterozygous PS-82 BO5 line of mice identified using a transgene specific PCR assay were backcrossed to the parental FVB/N strain (N = 10) to establish congenic line with homogeneous background strain. The line B05 has 30 copies of the transgene PS-82. Transgenic mice of the B05 line develop progressive loss of Purkinje cells and cerebellar function. Heterozygous B05
Results
To determine if a single dose of radiolabeled IGF-I will pass through the nasal passage into CNS, [125I]-IGF-I was administered intranasally to 5-week old wildtype mice. [125I]-IGF-I administration resulted in accumulation of radioactive IGF-I in various regions of the brain validating the route of IGF-I transport (Fig. 1). Maximum radioactivity was detected in the olfactory bulb followed by frontal cortex, brain stem and cerebellum. These observations are in agreement with earlier reports on
Discussion
The suppression of degenerative effects that mutant ataxin-1 exerts on Purkinje cells of SCA1 mice was investigated in this study following intranasal administration of IGF-I.
Acknowledgements
This work was supported by The National Institute of Neurological Disorders and Stroke, USA (Grant RO1 NS41546) and Lucky Day Foundation, USA.
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