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Purpose: To assess the optimal interval of preoperative intravitreal bevacizumab (IVB) administration in diabetic subjects undergoing pars plana vitrectomy (PPV) for severe manifestations of active proliferative diabetic retinopathy (PDR)., Design: Randomized clinical trial., Methods: One hundred and fifty-six patients with PDR-related complications requiring PPV were prospectively randomized into 1 of 2 treatment groups: Group A received IVB (2.5 mg/0.1 mL) 1-3 days before PPV, while Group B received IVB (2.5 mg/0.1 mL) 5-10 days before PPV. The primary outcome was best-corrected visual acuity (BCVA) at 6 months follow-up. Secondary outcome measures were intraoperative surgery time, intraoperative complications, postoperative complications, and incidence of unplanned PPV at 6 months follow-up., Results: One hundred and twenty-five subjects underwent PPV and completed the 6-month follow-up interval. Group B patients had better final BCVA (P = .033) and were less likely to have a postoperative complication (P = .018) when compared to Group A patients. The mean difference in final BCVA between groups was 0.22 logMAR (95% confidence interval: 0.02-0.43, P = .017). Group A was 3.90 (95% confidence interval: 1.08-17.31, P = .046) times more likely to have a loss of 1 or more logMAR lines of final BCVA when compared to Group B. There were no significant differences among the treatment groups with regard to baseline features, intraoperative surgery time, intraoperative complications, and incidence of unplanned PPV during the study interval., Conclusions: This randomized clinical trial demonstrated better postoperative outcomes at 6 months when subjects received preoperative IVB 5-10 days before PPV compared to 1-3 days for the treatment of PDR-related complications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Insulin-like growth factors (IGFs) are important modulators of organismal life-span all along phylogeny. These growth factors are widely viewed as detrimental for long life by reducing tissue resistance to oxidative stress. However, IGF-I has been consistently shown to be a potent neuroprotective factor in mammals, and as such, a deterrent of brain aging. Conversely, recent data suggest that IGF-I may contribute to amyloid neurodegeneration underlying Alzheimer's disease. These opposing observations underline an incomplete understanding of the significance of this ancestral hormone pathway in relation to brain aging. It is possible that these opposite results are the consequence of using different experimental approaches. Thus, brain amyloid injury is reduced in mutant mice partially defective in IGF-I receptor function, whereas IGF-I is neuroprotective when administered to animal models of neurodegenerative disease or normal brain aging. This approach-dependent effect of IGF-I highlights a fundamental gap in our knowledge of the relationship between peripheral and brain IGF-I function and the actual biological impact of experimental modulation of brain IGF-I function. We suggest to directly address brain IGF-I function in the varying experimental approaches used to confirm that changes have taken place in the desired way., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Peripheral and central diabetic neuropathies were studied in streptozotocin-diabetic rats, using behavioral, biochemical and electrophysiological techniques. Diabetic rats showed thermal hypoalgesia and decreasing motor nerve conduction velocity at 4 and 8 weeks of diabetes. In addition, amplitude of the evoked potential recorded in primary somatosensory cortex after stimulation of the sciatic nerve was markedly reduced at 8 weeks of diabetes. This decrease was accompanied by decreases in GluR2/3 AMPA receptor subunits. These changes seem to be specific to the somatosensory system and to originate in higher centers since they were not present in the hippocampus and were not observed at the level of gracilis nucleus. Insulin-like growth factor I (IGF-I) treatment reversed the reduced thermal sensitivity and peripheral nerve conduction velocity but did not reverse changes in the CNS, suggesting that once initiated, both anomalies may develop independently in this model of diabetic neuropathy. In conclusion, the results indicate that diabetes induces a wide spectrum of alterations in the central somatosensory system that are independent of the decreases in peripheral sensory transmission that could be responsible for the disturbances in somatosensory perception observed in diabetes.

Cellular and molecular processes leading to abnormal accumulation of beta amyloid in the brain are slowly being uncovered. A potential involvement of insulin and insulin-like growth factor I (IGF-I) in this plausible pathogenic process in Alzheimer's disease has recently been proposed. Evidence favoring this idea stems from the ability of both hormones to stimulate beta amyloid release from neurons as well as by the stimulatory effect that IGF-I exerts on brain amyloid clearance. In addition, insulin and IGF-I levels are altered in Alzheimer's patients and, probably in close association to these changes, cell sensitivity towards insulin--and possibly also IGF-I--is decreased in these patients. We now review evidence that disturbed insulin/IGF-I signaling to brain cells, initiated at the level of the blood-brain barriers is probably instrumental in development of brain amyloidosis. Furthermore, insulin and IGF-I are potent neuroprotective factors and can regulate levels of phosphorylated tau, a major component of neurofibrillary tangles found in Alzheimer's brains. Therefore, a decrease in trophic support to neurons together with increased tau phosphorylation will follow loss of sensitivity towards insulin and IGF-I. Altogether, this supports the notion that a single pathogenic event, i.e., brain resistance to insulin/IGF-I, accounts for neuronal atrophy/death, tangle formation and brain amyloidosis typical of Alzheimer's pathology.

The therapeutic potential of peptide growth factors as insulin-like growth factor I (IGF-I) is currently under intense scrutiny in a wide variety of diseases, including neurodegenerative illnesses. A new poly(lactic-co-glycolide)-based microsphere IGF-I controlled release formulation for subcutaneous (SC) delivery has been developed by a triple emulsion method. The resulting microspheres displayed a mean diameter of 1.5microm, with an encapsulation efficiency of 74.3%. The protein retained integrity after the microencapsulation process as evaluated by circular dichroism and SDS-PAGE. The administration of IGF-I in microspheres caused at least a 30-fold increase in IGF-I mean residence time in rats and mice when compared with the conventional SC solution. Therefore, dosing can be changed from the conventional twice a day to once every 2 weeks. Therapeutic efficacy of this new formulation has been studied in mutant mice with inherited Purkinje cell degeneration (PCD). These mice show a chronic limb discoordination that is resolved after continuous systemic delivery of IGF-I. Normal motor coordination was maintained as long as IGF-I microsphere therapy is continued. Moreover, severely affected PCD mice, with marked ataxia, muscle wasting and shortened life-span showed a significant improvement after continuous IGF-I microsphere therapy as determined by enhanced motor coordination, marked weight gain and extended survival. This new formulation can be considered of great therapeutic promise for some chronic brain diseases.

Although development of transgenic animals overexpressing insulin-like growth factor-I has allowed the establishment of a role of this trophic factor in brain growth, detailed knowledge of the action of insulin-like growth factor-I on different brain areas is still lacking. We now provide evidence for a pleiotrophic role of this growth factor on cerebellar development. Insulin-like growth factor-I produced by cerebellar cultures is a survival factor for Purkinje cells and a mitogen/differentiation factor for cerebellar glioblasts. Trophic effects of insulin-like growth factor-I were observed only during specific developmental stages. In addition, insulin-like growth factor-I increased intracellular Ca2+ levels in Purkinje cells and c-Fos in dividing glioblasts. Survival-promoting effects of insulin-like growth factor-I on Purkinje cells required activation of protein kinase C, while glioblast division induced by insulin-like growth factor-I depended on phosphatidylinosytol 3-kinase activation. We conclude that insulin-like growth factor-I is a paracrine/autocrine pleiotrophic factor for both glia and neurons in the cerebellum. Its effects are mediated by distinct intracellular signals and appear to be specific to the developmental stage of the target cell. Since development of the different cell populations that compose a specific brain territory is not synchronized, the pleiotrophic action of growth factors such as insulin-like growth factor-I may be essential to ontogenetic processes underlying normal brain growth.

Gonadal hormones exert a critical influence over the architecture of specific brain areas affecting the formation of neuronal contacts. Cellular mechanisms mediating gonadal hormone actions on synapses have been studied extensively in the rat arcuate nucleus, a hypothalamic center involved in the feed-back regulation of gonadotropins. Gonadal steroids exert organizational and activational effects on arcuate nucleus synaptic connectivity. Perinatal testosterone induces a sexual dimorphic pattern of synaptic contacts. Furthermore, during the preovulatory and ovulatory phases of the estrous cycle there is a transient disconnection of inhibitory synaptic inputs to the somas of arcuate neurons. This synaptic remodeling is induced by estradiol, blocked by progesterone, and begins with the onset of puberty in females. Astroglia appear to play a significant role in the organizational and the activational hormone effects on neuronal connectivity by regulating the amount of neuronal membrane available for the formation of synaptic contacts and by releasing soluble factors, such as insulin-like growth factor I (IGF-I), which promote the differentiation of neural processes. Recent evidence indicates that gonadal steroids and IGF-I may interact in their trophic effects on the neuroendocrine hypothalamus. Estradiol and IGF-I promote the survival and morphological differentiation of rat hypothalamic neurons in primary cultures. The effect of estradiol depends on IGF-I, while the effects of both estradiol and IGF-I depend on estrogen receptors. Furthermore, estrogen activation of astroglia in hypothalamic tissue fragments depends on IGF-I receptors. These findings indicate that IGF-I may mediate some of the developmental and activational effects of gonadal steroids on the brain and suggest that IGF-I may activate the estrogen receptor to induce its neurotrophic effects on hypothalamic cells. In addition, IGF-I levels in the neuroendocrine hypothalamus are regulated by gonadal steroids. IGF-I levels in tanycytes, a specific astroglia cell type present in the arcuate nucleus and median eminence, increase at puberty, are affected by neonatal androgen levels, show sex differences, and fluctuate in accordance to the natural variations in plasma levels of ovarian steroids that are associated with the estrous cycle. These changes appear to be mediated by hormonal regulation of IGF-I uptake from blood or cerebrospinal fluid by tanycytes. These results suggest that tanycytes may be involved in the regulation of neuroendocrine events in adult rats by regulating the availability of IGF-I to hypothalamic neurons. In summary, IGF-I and different forms of neuron-astroglia communication are involved in the effects of estradiol on synaptic plasticity in the hypothalamic arcuate nucleus.

Insulin-like growth factor I participates in the cellular response to brain insult by increasing its messenger RNA expression and/or protein levels in the affected area. Although it has been suggested that insulin-like growth factor I is involved in a variety of cellular responses leading to homeostasis, mechanisms involved in its possible trophic effects are largely unknown. Since activation of c-Fos in postmitotic neurons takes place both in response to insulin-like growth factor I and after brain injury, we have investigated whether this early response gene may be involved in the actions of insulin-like growth factor I after brain insult. Partial deafferentation of the cerebellar cortex by 3-acetylpyridine injection elicited c-Fos protein expression on both Purkinje and granule cells of the cerebellar cortex. This neurotoxic insult also triggered gliosis, as determined by an increased number of glial fibrillary acidic protein-positive cells (reactive astrocytes) in the cerebellar cortex. When 3-acetylpyridine-injected animals received a continuous intracerebellar infusion of either a peptidic insulin-like growth factor I receptor antagonist or an insulin-like growth factor I antisense oligonucleotide for two weeks through an osmotic minipump, c-Fos expression was obliterated while reactive gliosis was greatly increased. On the contrary, continuous infusion of insulin-like growth factor I significantly decreased reactive gliosis without affecting the increase in c-Fos expression. These results indicate that insulin-like growth factor I is involved in both the neuronal (c-Fos) and the astrocytic (glial fibrillary acidic protein) activation in response to injury.

Neurotrophic effects of estradiol and insulin-like growth factor-I were assessed in primary cultures from fetal rat hypothalamus. Cultured neurons were immunostained with an antibody for the microtubule-associated protein-2. While both estradiol and insulin-like growth factor-I increased the number of microtubule-associated protein-2-immunoreactive neurons and the extension of immunoreactive processes, the effect of these two factors was not additive. The estradiol-induced increases in neuronal numbers and extension of neuronal processes were blocked by either the estrogen receptor antagonist ICI 182,780 or by an anti-sense oligonucleotide to the estrogen receptor. Furthermore, incubation of the cultures with an anti-sense oligonucleotide directed against the insulin-like growth factor-I messenger RNA also blocked the effect of estradiol. In turn, the effects of insulin-like growth factor-I were blocked by the estrogen receptor antagonist ICI 182,780 and by the anti-sense oligonucleotide to the estrogen receptor. These findings suggest that estradiol-induced activation of the estrogen receptor in developing hypothalamic cells requires the presence of insulin-like growth factor-I, and that both estradiol and insulin-like growth factor-I use the estrogen receptor as a mediator of their trophic effects on hypothalamic neurons.

Insulin-like growth factor-I elicits a long-term depression of the glutamate-induced GABA release in the adult rat cerebellum that lasts at least several hours. We studied whether protein kinase C and nitric oxide may be involved in this effect of insulin-like growth factor-I on GABA release since both signalling pathways have been implicated in other forms of neuromodulation in the cerebellum. By using microdialysis in the adult rat cerebellum, we found that either an inhibitor of protein kinase C (staurosporine) or of nitric oxide synthase (Nw-nitro-L-arginine methyl ester) counteracted the long-term, but not the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. On the contrary, when either an activator of protein kinase C (phorbol ester), or an nitric oxide donor (L-arginine), were given with glutamate, they mimicked only the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. Finally, when both protein kinase C and nitric oxide-synthase were simultaneously inhibited by conjoint administration of staurosporine and Nw-nitro-L-arginine methyl ester, a complete blockage of both the short and the long-term effects of insulin-like growth factor-I on GABA release was obtained. These results, indicate that: (i) activation by insulin-like growth factor-I of either the protein kinase C or nitric oxide-signalling pathways is sufficient for the short-term inhibition of glutamate-induced GABA release; and (ii) simultaneous activation of both the protein kinase C and the nitric oxide signalling pathways is necessary for insulin-like growth factor-I to induce a long-term depression of GABA responses to glutamate. Thus, long-term depression of glutamate-induced GABA release by insulin-like growth factor-I in the cerebellum is mediated by simultaneous activation of both protein kinase C and nitric oxide-signalling pathways.

The hypothesis that insulin-like growth factor-I is a trophic factor for primary fetal rat hypothalamic cells was tested, since we previously reported a potent mitogenic effect of this peptide on virally-transformed hypothalamic cells. It was found that insulin-like growth factor-I produced significant and dose-dependent increases in the survival of fetal hypothalamic neurons in primary mixed glial/neuronal cultures. By 48 h in vitro, cultures treated with insulin-like growth factor-I (6 nM) had twice as many neurite-bearing cells as controls, while by day 15 a five-fold difference was present. The peptide was similarly active in promoting neuronal survival in neuron-enriched (98% neurons) hypothalamic cultures. Mixed hypothalamic cultures had specific binding sites for insulin-like growth factor-I. In addition, the neurons grown in the presence of insulin-like growth factor-I had a more differentiated morphology and had significantly higher levels of protein kinase C, an enzyme that increases during neurite formation and synaptogenesis. Finally, glial-enriched cultures (greater than 99% glial cells) obtained from the fetal hypothalamus showed increased [3H]thymidine incorporation in response to insulin-like growth factor-I. These results further support the contention that insulin-like growth factor-I is a neurotrophic factor and suggest that it may participate in the normal development of the hypothalamus by increasing neuronal survival/differentiation and stimulating glial growth.