Re: RESEARCH: Insulin-Like Growth Factors

May 30, 2002

Pam,

You are such an incredible resource person! I see Dr. Lee's 1996 work in

the group of articles, but I think he published subsequent reports after the

1996 paper. And, it was IGF-1 that he was working on. In any event, I am

struck that (more so than most of what we see in the way research on MSA)

these articles have a noticeably optimist tone to them regarding potential

for the research to prove effective. I am surprised that we aren't hearing

more on this topic.

Regards,

Jerry Cash

RESEARCH: Insulin-Like Growth Factors

Neurobiol Dis 2000 Dec;7(6 Pt :657-65

Neurodegeneration is associated to changes in serum insulin-like growth

factors.

Busiguina S, Fernandez AM, Barrios V, R, Tolbert DL, Berciano J,

-Aleman I.

Laboratory of Neuroendocrinology, Cajal Institute, Madrid, Spain.

Serum levels of insulin and insulin-like growth factors and their binding

proteins (IGFs and IGFBPs, respectively) are changed in human

neurodegenerative diseases of very different etiology, such as Alzheimer's

disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the

significance of these endocrine disturbances is not clear. We now report

that in two very different inherited neurodegenerative conditions,

ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease,

serum levels of IGFs are also altered. Both types of patients have increased

serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while

only AT patients have high serum insulin levels. Furthermore, serum IGFs are

also changed in three different animal models of neurodegeneration:

neurotoxin-induced motor discoordination, diabetic neuropathy, and

hereditary cerebellar ataxia. In these three models, serum insulin levels

are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are

decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is

increased in hereditary ataxic rats. Altogether, these observations indicate

that a great variety of neurodegenerative diseases show endocrine

perturbations, resulting in changes in serum IGFs levels. These

perturbations are disease-specific and are probably due to metabolic and

endocrine derangements, nerve cell death, and sickness-related disturbances

associated to the neurodegenerative process. Our observations strongly

support the need to evaluate serum IGFs in other neurodegenerative

conditions.

----------------

Eur J Neurosci 1999 Jun;11(6):2019-30

Neuroprotective actions of peripherally administered insulin-like growth

factor I in the injured olivo-cerebellar pathway.

Fernandez AM, de la Vega AG, Planas B, -Aleman I.

Laboratory of Cellular and Molecular Neuroendocrinology, Cajal Institute,

CSIC, Madrid, Spain.

Exogenous administration of insulin-like growth factor I (IGF-I) restores

motor function in rats with neurotoxin-induced cerebellar deafferentation.

We first determined that endogenous IGFs are directly involved in the

recovery process because infusion of an IGF-I receptor antagonist into the

lateral ventricle blocks gradual recovery of limb coordination that

spontaneously occurs after partial deafferentation of the olivo-cerebellar

circuitry. We then analysed mechanisms whereby exogenous IGF-I restores

motor function in rats with complete damage of the olivo-cerebellar pathway.

Treatment with IGF-I normalized several markers of cell function in the

cerebellum, including calbindin, glutamate receptor 1 (GluR1),

gamma-aminobutyric acid (GABA) and glutamate, which are all depressed after

3-acetylpyridine (3AP)-induced deafferentation. IGF-I also promoted

functional reinnervation of the cerebellar cortex by inferior olive (IO)

axons. In the IO, increased expression of bax in neurons and bcl-X in

astrocytes after 3AP was significantly reduced by IGF-I treatment. On the

contrary, IGF-I prevented the decrease in poly-sialic-acid neural cell

adhesion molecule (PSA-NCAM) and GAP-43 expression induced by 3AP in IO

cells. IGF-I also significantly increased the number of neurons expressing

bcl-2 in brainstem areas surrounding the IO. Altogether, these results

indicate that subcutaneous IGF-I therapy promotes functional recovery of the

olivo-cerebellar pathway by acting at two sites within this circuitry: (i)

by modulating death- and plasticity-related proteins in IO neurons; and (ii)

by impinging on homeostatic mechanisms leading to normalization of cell

function in the cerebellum. These results provide insight into the

neuroprotective actions of IGF-I and may be of practical consequence in the

design of new therapeutic approaches for neurodegenerative diseases.

PMID: 10336671 [PubMed - indexed for MEDLINE]

-------------

Proc Natl Acad Sci U S A 1998 Feb 3;95(3):1253-8

Insulin-like growth factor I restores motor coordination in a rat model of

cerebellar ataxia.

Fernandez AM, de la Vega AG, -Aleman I.

Laboratory of Cellular and Molecular Neuroendocrinology, Instituto Cajal,

Consejo Superior de Investigaciones Cientificas, Madrid 28002, Spain.

We tested the potential of insulin-like growth factor I (IGF-I) to induce

functional recovery in an animal model of cerebellar ataxia because this

motor impairment is accompanied in humans and rodents by distinct changes in

several components of the IGF-I trophic system. Rats rendered ataxic by

deafferentation of the cerebellar cortex with 3-acetylpyridine recovered

motor function after IGF-I was administered, as determined by behavioral and

electrophysiological tests. When treated with IGF-I, inferior olive neurons,

the targets of the neurotoxin, were rescued to various degrees (from 92 to

27% of surviving neurons), depending on the time that treatment with IGF-I

was initiated. Furthermore, full recovery was obtained regardless of the

route by which the trophic factor was administered (intraventricular or

subcutaneous) even in rats with severe neuronal loss. These results suggest

that human ataxia could be treated with IGF-I by a simple procedure.

PMID: 9448318 [PubMed - indexed for MEDLINE]

----------

Brain Res 1999 Jul 24;835(2):306-14

Mucus of the human olfactory epithelium contains the insulin-like growth

factor-I system which is altered in some neurodegenerative diseases.

Federico G, Maremmani C, Cinquanta L, Baroncelli GI, Fattori B, Saggese G.

Endocrine Unit, Division of Paediatrics, Department of Reproductive Medicine

and Paediatrics, University of Pisa, Via Roma 67, I-56125, Pisa, Italy.

Growth factors are believed to be involved in the mitotic regulation of the

animal olfactory epithelium (OE). We investigated mucus covering the human

OE area to see if it contained the insulin-like growth factor-I (IGF-I) and

its binding proteins (IGFBPs) and to examine their behaviour in

neurodegenerative diseases. Thirty patients with idiopathic late onset

cerebellar ataxia (ILOCA), Parkinson's disease, and amyotrophic lateral

sclerosis (ALS) and 30 age- and sex-matched healthy subjects were studied.

In 10 controls, we also analyzed the mucus of the respiratory mucosa of the

nose and tears. We detected IGF-I in the mucus covering the OE and Western

ligand blot analysis (WLB) showed IGFBPs with an apparent Mr of 41,

500/38,500, 34,000 and 24,000, which were immunoprecipitated by specific

antisera to IGFBP-3, -2 and -4, respectively. Their levels were higher than

those observed in the respiratory mucosa of the nose or in tears. Mucus of

the OE of the patients contained significantly reduced levels of IGF-I in

comparison with those of controls. The intensity of all the IGFBPs-related

bands were reduced in the ILOCA, while the remaining patients had a loss in

the amounts of IGFBP-3. Plasma IGF-I and IGFBPs levels were similar in

patients and controls. In conclusion, our data show that mucus covering the

human OE contains IGF-I and IGFBPs, suggesting that these factors have a

role in the activity of the OE. The amounts are reduced in the patients'

mucus, possibly reflecting a dysfunction of the OE itself.

PMID: 10415387 [PubMed - indexed for MEDLINE

------

http://qemnetwork.qem.org/Sharp%20Plus%20%202001Abstracts/C..html

Effects of Insulin-like Growth Factor-I on Motor Coordination In Calcium

Channel Mutant Mice

by

Mentor: Dr. Louise C. Abbott, Ph.D, D.V.M

The aim of this study is to investigate the effects of exogenous IGF-1

administration on movement control in tottering and leaner mice. Tottering

and leaner mice carry mutations in neuronal P/Q-type calcium ion channels.

Cerebellar P/Q-type calcium channels control synaptic transmission, which is

essential for proper neuIal control of movement and neuronal survival.

However, dysfunction of P/Q-type calcium channels in the central nervous

system of these mice may prevent normal synaptic transmission resulting in

the ataxia, absence sein~res and paroxysmal dyskinesia that these mice

exhibit. These animals can serve as models of human ataxia and movement

disorders, which could help, discover new treatments for these disorders.

Insulin-like growth factor-l (IGF-1) has many important roles in

development. IGFl is mainly produced in the liver and transported to other

organs inciuding the brain. IGF-1 is especially important in learning,

memory, and cerebellum. Reports have shown that a decreased concentration of

IGF-1 occurs in human ataxia patients and in animal models of ataxia.

Moreover, exogonous IGF-1 administration improves motor function in animal

models of ataxia. Previous experiments showed that at postnatal day 30 serum

and cerebellar IGF-1 concentrations in tottering and leaner mice are lower

than normal mice, suggesting that decreased IGF-1 may play a role in the

ataxia that these mice exbibit. Wild type, tottering and leaner mice were

given lactated Ringer's saline (LRS), acetic acid only or IGFl plus acetic

acid subcutaneously, once daily, for 4 weeks. Improvement of cerebellar

motor control was evaluated by open field, balance rod and gait print tests.

The open field test uses a rectangular box to measure exploratory behavior

and activity. The balance rod test assesses basic coordination by measuring

the length of time mice can stay on the rod. Whereas, the gait test measures

how coordinated the mice are able to walk. At the time of abstract

submission the control group, which received LRS alone, was the only group

completed. The wild type mice included in this control group seemed to have

no significant affect from daily administration of LRS. The wild type mice

also proved to be more active than the tottering and leaner mice throughout

all the behavioral tests. The leaner mice showed slight improvement as they

grew older, but they were still slow, inactive and severely ataxic. The

tottering mice showed no improvement. The studies using mice receiving IGF-I

plus acetic acid or acetic acid alone were still in progress.

----------

Ann Neurol 1996 Mar;39(3):335-42

The insulin-like growth factor I system in cerebellar degeneration.

-Aleman I, Barrios V, Lledo A, Berciano J.

Laboratory of Cellular and Molecular Neuroendocrinology, Cajal Institute,

CSIC, Madrid, Spain.

Brain insulin-like growth factor I (IGF-I) and its related molecules may be

involved in neurodegenerative processes in which IGF-I-containing pathways

are compromised. Since IGF-I is present in the olivocerebellar circuitry,

two types of late-onset cerebellar ataxias (olivopontocerebellar and

idiopathic cerebellar cortical atrophy) were chosen to test this hypothesis.

The following significant changes in the peripheral IGF-I system of these

patients were found: low IGF-I levels, and high IGF-binding protein 1

(BP-1), and BP-3 affinity for IGF-1. Sixty percent of the patients also had

significantly low insulin levels. Patients suffering from other neurological

diseases with cerebellar dysfunction and ataxia not involving the

olivocerebellar pathway also had low IGF-I levels, while IGFBPs and insulin

levels were normal. Our data indicate that degeneration of an

IGF-I-containing neuronal pathway produces significant changes in the

peripheral IGF system. This suggests strongly that the endocrine

(bloodborne) and the paracrine/autocrine (brain) IGF systems are linked

functionally. We propose that alterations in the blood IGF-I system may

constitute a marker of some cerebellar diseases.

PMID: 8602752 [PubMed - indexed for MEDLINE]

----

Nat Med 1996 Jan;2(1):65-71

Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I

system genes and partially restore behavioral function.

Zhang W, Lee WH, Triarhou LC.

Department of Anatomy, Indiana University School of Medicine, Indianapolis

46202, USA.

Fetal grafts of normal cerebellar tissue were implanted into the cerebellum

of Purkinje cell degeneration mutant mice (pcd/pcd), a model of adult-onset

recessively inherited cerebello-olivary atrophy, in an attempt at correcting

their cellular and motor impairment. Donor cerebellar cells engrafted in the

appropriate sites, as evidenced by the pattern of expression of insulin-like

growth factor-I (IGF-I) system genes. Bilateral cerebellar grafts led to an

improvement of motor behaviors in balance rod tests and in the open field,

providing evidence for functional integration into the atrophic mouse

cerebellum and underscoring the potential of neural transplantation for

counteracting the human cerebellar ataxias.

PMID: 8564845 [PubMed - indexed for MEDLINE]

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May 30, 2002