Circulating insulin-like growth factor I mediates effects of exercise on the brain

Physical exercise increases brain activity through mechanisms not yet known. We now report that in rats, running induces uptake of blood insulin- like growth factor I (IGF-I) by specific groups of neurons throughout the brain. Neurons accumulating IGF-I show increased spontaneous firing and a protracted increase in sensitivity to afferent stimulation. Furthermore, systemic injection of IGF-I mimicked the effects of exercise in the brain. Thus, brain uptake of IGF-I after either intracarotid injection or after exercise elicited the same pattern of neuronal accumulation of IGF-I, an identical widespread increase in neuronal c-Fos, and a similar stimulation of hippocampal brain-derived neurotrophic factor. When uptake of IGF-I by brain cells was blocked, the exercise-induced increase on c-Fos expression was also blocked. We conclude that serum IGF-I mediates activational effects of exercise in the brain. Thus, stimulation of the uptake of blood-borne IGF-I by nerve cells may lead to novel neuroprotective strategies.Peer Reviewe

Sexual dimorphism and sex steroid modulation of glial fibrillary acidic protein messenger RNA and immunoreactivity levels in the rat hypothalamus

By using the techniques of in situ hybridization histochemistry and immunocytochemistry, we have found that both glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive Surface density in the arcuate nucleus and median eminence are modulated by both the neonatal and adult sex steroid environments. No effect was seen on the number of immunoreactive glia. Intact adult males had significantly higher glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive surface density than females. Both adult and neonatal castration of male animals significantly reduced glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive surface density. Neonatal and adult testosterone treatment increased both of these parameters in both sexes; however, there was no additive effect of the steroid treatments. Glial cells are involved in the proliferation, survival, migration and maturation of neurons, as well as in the modulation of synaptic connectivity, and therefore it follows that hormonal modulation of glia may mediate some of the known steroid effects on neurons. The data reported here show that astroglia are significantly influenced by both the neonatal and adult sex steroid environments and suggest that some of the steroid effects on neurons during both of these developmental periods may be mediated, at least in part, through modulation of glial cells.Peer Reviewe

Insulin-like growth factor I is an afferent trophic signal that modulates calbindin-28kD in adult Purkinje cells

Recent evidence suggests that Purkinje cells are specific targets of insulin-like growth factor I (IGF-I) through their entire life span. During development, Purkinje cell numbers and their calbindin-28kD content increase after IGF-I treatment in culture. In the adult, part of the IGF-I present in the cerebellum is transported from the inferior olive, and modulates Purkinje cell function. We investigated whether IGF-I produced by inferior olive neurons and transported to the contralateral cerebellum through climbing fibers may modulate the levels of calbindin-28kD in the cerebellum of adult animals. Twenty-four hr after injection of an antisense oligonucleotide of IGF-I into the inferior olive, both IGF-I and calbindin-28kD levels in the contralateral cerebellar lobe were significantly reduced, while the number of calbindin-positive Purkinje cells was unchanged. The effect of the antisense on IGF-I levels was fully reversed 3 days after its injection into the inferior olive, with a postinhibitory rebound observed at this time, while calbindin-28kD levels slowly returned to control values. A control oligonucleotide did not produce any change in either IGF-I or calbindin-28kD content in the cerebellum. These results indicate that normal levels of IGF- I in the inferior olive are necessary to maintain appropriate levels of IGF- I in the cerebellum and of calbindin-28kD in the Purkinje cell. These results also extend our previous findings on the existence of an olivo-cerebellar IGF-I-containing pathway with trophic influence on the adult Purkinje cell.Peer Reviewe

Specific alterations of the insulin-like growth factor I system in the cerebellum of diabetic rats

Specific changes in circulating levels of insulin-like growth factor I (IGF-I) and various IGF-binding proteins are known to occur in insulin dependent diabetic patients and laboratory animals. However, little attention has been paid to the effects of this chronic metabolic disease on the IGF system of the central nervous system. Because various types of human cerebellar degeneration are accompanied by changes in the peripheral IGF-I system which are similar, although not identical, to those found in diabetes, we tested whether diabetes results in changes in the cerebellar IGF-I system. Streptozotocin-induced diabetic rats were divided into two groups: 1) well controlled diabetics, which received twice daily injections of insulin and had mean glucose levels in the normal range; and 2) poorly controlled diabetic animals, which received 1 U of insulin once a day and had glucose levels above 300 mg/dl. As previously described, there were significant decreases in circulating levels of IGF-I and IGFBP-3 (38-42 kDa band), and an increase in the 30-kDa IGFBP (likely corresponding to IGFBF-1) in poorly controlled diabetic animals. All these parameters were normal in well controlled diabetic rats. In addition, significant modifications in the cerebellar IGF-I system were found. Poorly controlled diabetic animals had significantly lower levels of IGF-I protein in the cerebellum, whereas no change in cerebellar IGF-I messenger RNA (mRNA) levels was found. A significant reduction in IGFBP-2 (31 kDa-band) protein and mRNA levels was also found in poorly controlled diabetics. Well controlled rats had normal cerebellar IGF-I levels, whereas levels of IGFBP-2 protein and mRNA were still significantly low. Finally, mRNA levels for the IGF-I receptor were similar in all experimental groups. These changes appear to be anatomically specific because other brain areas did not show the same alterations. The present results indicate that in the diabetic animal changes in circulating IGF-I and IGFBPs are accompanied by, and possibly implicated in, modifications of the IGF-I system in the cerebellum and possibly other brain regions. We suggest that modifications in the cerebellar IGF-I system, which plays an important trophic role in postnatal life, may underlie, at least in part, specific neuronal losses known to occur in diabetic patients.Peer Reviewe

Anatomically specific changes in the expression of somatostatin, growth hormone-releasing hormone and growth hormone receptor mRNA in diabetic rats

Growth hormone (GH) secretion is altered in poorly controlled diabetic animals. However, modifications in the hypothalamic neuropeptides that control GH secretion, somatostatin and GH-releasing hormone (GHRH), as well as changes in the sensitivity of the hypothalamus and pituitary to the feedback effects of GH, are less clear. We have used RNase protection assays and in-situ hybridization to address whether the mRNA expression of GH, somatostatin and GHRH, as well as of the GH receptor (GHR) in the hypothalamus and anterior pituitary, are altered in streptozotocin-induced diabetic rats. After induction of diabetes, rats were treated with insulin twice daily for 3 weeks to obtain either poorly controlled (mean plasma glucose > 300 mg/dl) or well-controlled diabetic rats. Although no significant change in pituitary GH mRNA expression was found, the hypothalamic expression of GHRH and somatostatin mRNA was reduced in poorly-controlled diabetic rats and returned to control values with normalisation of plasma glucose concentrations (P < 0.0001 and P < 0.002, respectively). Somatostatin mRNA expression was reduced only in the central portion of the periventricular nucleus, with no change being seen in the other areas of the periventricular nucleus or in the arcuate, suprachiasmatic or paraventricular nuclei. A significant decline in GHRH mRNA expression was observed in both the arcuate nucleus and ventromedial hypothalamus. Anterior pituitary GHR mRNA expression was significantly reduced in both well and poorly-controlled diabetic rats, while there was no change in the hypothalamus. To examine whether the evolution time of the diabetes influences these parameters, in a subsequent experiment, diabetic rats received no insulin for 2 months. A significant decline in GHRH and somatostatin mRNA expression was also observed in these rats. In addition, pituitary GH mRNA expression declined significantly in long-term diabetic rats. These results demonstrate that: (1) the expression of both GHRH and somatostatin declines specifically in anatomical areas involved in anterior pituitary hormone control; (2) GHR mRNA expression is decreased in the pituitary of diabetic rats, but not in the hypothalamus, and does not return to control values with normalisation of mean blood glucose concentrations; and (3) the evolution time of the diabetes is important for detecting some changes, including the decrease in pituitary GH mRNA expression.Peer Reviewe

Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy

Physical exercise ameliorates age-related neuronal loss and is currently recommended as a therapeutical aid in several neurodegenerative diseases. However, evidence is still lacking to firmly establish whether exercise constitutes a practical neuroprotective strategy. We now show that exercise provides a remarkable protection against brain insults of different etiology and anatomy. Laboratory rodents were submitted to treadmill running (1 km/d) either before or after neurotoxin insult of the hippocampus (domoic acid) or the brainstem (3-acetylpyridine) or along progression of inherited neurodegeneration affecting the cerebellum (Purkinje cell degeneration). In all cases, animals show recovery of behavioral performance compared with sedentary ones,i.e., intact spatial memory in hippocampal-injured mice, and normal or near to normal motor coordination in brainstem- and cerebellum-damaged animals. Furthermore, exercise blocked neuronal impairment or loss in all types of injuries. Because circulating insulin-like growth factor I (IGF-I), a potent neurotrophic hormone, mediates many of the effects of exercise on the brain, we determined whether neuroprotection by exercise is mediated by IGF-I. Indeed, subcutaneous administration of a blocking anti-IGF-I antibody to exercising animals to inhibit exercise-induced brain uptake of IGF-I abrogates the protective effects of exercise in all types of lesions; antibodyt-reated animals showed sedentary-like brain damage. These results indicate that exercise prevents and protects from brain damage through increased uptake of circulating IGF-I by the brain. The practice of physical exercise is thus strongly recommended as a preventive measure against neuronal demise. These findings also support the use of IGF-I as a therapeutical aid in brain diseases coursing with either acute or progressive neuronal death.Peer Reviewe

Neurodegeneration is associated to changes in serum insulin-like growth factors

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- 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- 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. © 2000 Academic Press.Peer Reviewe

Agonist-specific and sexual stage-dependent inhibition of gonadotropin-releasing hormone-stimulated gonadotropin and growth hormone release by ryanodine: Relationship to sexual stage-dependent caffeine-sensitive hormone release

Differential utilization of intracellular Ca2+ stores with specific functional characteristics could be a potential mechanism for coupling various stimuli to specific cellular responses. In the goldfish pituitary, both gonadotropes and somatotropes possess multiple intracellular Ca2+ stores that are differentially coupled to agonist-evoked exocytosis. We investigated the role of ryanodine receptor/Ca2+-release channels (RyR) in basal and gonadotropin-releasing hormone (GnRH)-evoked hormone secretion from cultured gonadotropes and somatotropes using radioimmunoassay for gonadotropin (GTH-II) and growth hormone (GH). As is the case in vivo, the basal and evoked secretion of both hormones varied with seasonal reproductive status. GnRH-stimulated hormone release was three-fold higher in cells from sexually mature animals compared to those in a sexually regressed state. Nanomolar doses of ryanodine evoked significant GTH-II and GH secretion, suggesting that ryanodine-sensitive Ca2+ stores can couple to exocytosis in both cell types. In gonadotropes, 10 μM ryanodine abolished cGnRH-II-evoked GTH-II release in both sexually mature and sexually regressed fish, while sGnRH signalling was mediated by ryanodine-sensitive Ca2+ stores in cells from sexually regressed fish only. Ryanodine-sensitive Ca2+ stores in somatotropes were only involved in cGnRH-II-stimulated GH release during gonadal regression. In contrast, sGnRH-stimulated, but not cGnRH-II-stimulated, GH release was significantly reduced by 1 μM xestospongin C. Although hormone release stimulated by mobilizing caffeine-sensitive Ca2+ pools was also markedly seasonal, it was largely independent of ryanodine-sensitive Ca2+ stores. Ryanodine-sensitive Ca2+ stores in both cell types are not active downstream of ionomycin, BayK 8644, protein kinase C or cyclic adenosine monophosphate signalling pathways, suggesting difference from a classical Ca2+-induced Ca2+ release system. Ours study is the first to suggest that RyR2 may be involved in the seasonal plasticity of pituitary function, which may be related to cyclic changes observed in reproduction and growth.Peer Reviewe