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Although vascular dysfunction is a major suspect in the etiology of several important neurodegenerative diseases, the signals involved in vessel homeostasis in the brain are still poorly understood. We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxia-inducible factor 1[alpha] and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain. Low serum/brain IGF-I levels that are associated with old age and with several neurodegenerative diseases may be related to an increased risk of vascular dysfunction.

Tests the potential of insulin-like growth factor I (IGF-I) to induce functional recovery in an animal model of cerebellar ataxia. Reasons why these tests were done; Reference made to motor pathways in the cerebellum; Evaluation of motor coordination; Conclusions reached.

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N -acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.

The cerebellum is thought to be critically involved in learning and retention of several types of classically conditioned motor responses. We investigated whether insulin-like growth factor I (IGF-I) may constitute an intercellular mediator of a motor learning task because previous findings indicated that IGF-I from the inferior olive modulates glutamate-induced gamma-aminobutyric acid release by Purkinje cells in the cerebellar cortex. Synaptic plasticity of the Purkinje cell is thought to be instrumental in motor learning. We found that injection of an IGF-I antisense oligonucleotide in the inferior olive elicited a complete inhibition of conditioned eye-blink learning in freely moving rats. This blockage was reversible and recovered when the levels of cerebellar IGF-I returned to normal values. Injection of a sense oligonucleotide did not interfere with the acquisition of the conditioned response. On the other hand, retention of the conditioned response was not impaired by subsequent injection of the IGF-I antisense oligonucleotide, indicating that olivocerebellar IGF-I is essential for the acquisition of the conditioned eye-blink response but is not essential for its retention.

We tested the possibility that insulin-like growth factor I (IGF-I) acts as a neuromodulator in the adult cerebellar cortex since previous observations indicated that IGF-I is located in the olivo-cerebellar system encompassing the inferior olive and Purkinje cells. We found that conjoint administration of IGF-I and glutamate through a microdialysis probe stereotaxically implanted into the cerebellar cortex and deep cerebellar nuclei greatly depressed the release of gamma-aminobutyric acid (GABA), which normally follows a glutamate pulse. This inhibition was dose-dependent and long-lasting. Moreover, the effect was specific for glutamate since KCl-induced GABA release was not modified by IGF-I. Basic fibroblast growth factor, another growth-related peptide present in the cerebellum, did not alter the response of GABA to glutamate stimulation. In addition, electrical stimulation of the inferior olivary complex significantly raised IGF-I levels in the cerebellar cortex. Interestingly, when the inferior olive was stimulated in conjunction with glutamate administration, GABA release by cerebellar cells in response to subsequent glutamate pulses was depressed in a manner reminiscent of that seen after IGF-I. These findings indicate that IGF-I produces a long-lasting depression of GABA release by Purkinje cells in response to glutamate. IGF-I might be present in climbing fiber terminals and/or cells within the cerebellar cortex and thereby might affect Purkinje cell function. Whether this IGF-I-induced impairment of glutamate stimulation of Purkinje cells underlies functionally plastic processes such as long-term depression is open to question.

The effect of long-term administration of analogs of luteinizing hormone-releasing hormone (LH-RH) and somatostatin on the growth of the growth hormone (GH)- and prolactin (PRL)-secreting rat pituitary GH3 tumor was investigated. Daily administration of [D-Trp6]LH-RH (50 micrograms/day), early after inoculation of the GH3 tumor, inhibited tumor growth by more than 90% as compared to controls. Similarly, in two experiments, a single once-a-month injection of long-acting [D-Trp6]LH-RH microcapsules (in a dose calculated to release about 25 micrograms/day for 30 days) inhibited the growth of GH3 pituitary tumor by more than 50% 6 or 13 wk after transplantation, when the tumors were fully developed. Serum GH and PRL levels also were reduced markedly by treatment with [D-Trp6]LH-RH. On the other hand, the administration of an antagonistic analog of LH-RH, N-Ac-[D-Phe(4Cl)1,2, D-Trp3, D-Arg6, D-Ala10]LH-RH, did not significantly reduce the growth of this tumor, and the treatment with two different analogs of somatostatin, cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) and D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr NH2, appeared to enhance it. These results are in agreement with previous findings of growth inhibition of 7315a pituitary tumors with different hormone-secreting characteristics by agonistic analogs of LH-RH. The collective data from experimental work with rat pituitary tumor models support the contention that the use of [D-Trp6]LH-RH might be considered for the treatment of some patients with pituitary tumors who failed to respond to conventional therapy.

We investigated the effects of [D-Trp6]LH-RH [agonistic analog of luteinizing hormone-releasing hormone (LH-RH)], N-Ac-[D-p-Cl-Phe1,2,D-Trp3,D-Phe6,D-Ala10]LH-RH (antagonistic analog), and [D-5-methoxy-Trp8]somatostatin (somatostatin analog) on the growth of the prolactin and corticotropin-secreting pituitary tumor 7315a in female Buffalo rats. Chronic administration of [D-Trp6]LH-RH in a dose of 25 micrograms/day, starting 18 days after inoculation with the tumor, inhibited the growth of the pituitary tumor. Tumor weight and volume also were reduced when this agonist was administered 3 days after inoculation. The antagonistic LH-RH analog, injected in a dose of 50-100 micrograms for 14-24 days, also significantly inhibited the growth of pituitary tumor. Chronic administration of the somatostatin analog in a dose of 25 micrograms twice a day likewise decreased tumor weights in comparison with controls. The inhibition of pituitary tumor growth by LH-RH agonist, LH-RH antagonist, and somatostatin analog was accompanied by a decrease in serum prolactin levels. It was concluded that LH-RH agonist, LH-RH antagonist, and somatostatin analog can inhibit the growth of estrogen-dependent prolactin/corticotropin-secreting pituitary tumor in rats.