A Coordinated Action of Blood-Borne and Brain Insulin-Like Growth Factor I in the Response to Traumatic Brain Injury.

In response to injury, the brain produces different neuroprotective molecules, such as insulin-like growth factor I (IGF-I). However, IGF-I is also taken up by the brain from the circulation in response to physiological stimuli. Herein, we analyzed in mice the relative contribution of circulating and locally produced IGF-I to increased brain IGF-I levels after insult. Traumatic brain injury (TBI) induced by a controlled impact resulted in increased IGF-I levels in the vicinity of the lesion, but mice with low serum IGF-I showed significantly lower increases. Indeed, in normal mice, peripheral IGF-I accumulated at the lesion site after injury, and at the same time serum IGF-I levels decreased. Collectively, these data suggest that serum IGF-I enter into the brain after TBI and contributes to increased brain IGF-I levels at the injury site. This connection between central and circulating IGF-I provides an amenable route for treatment, as subcutaneous administration of IGF-I to TBI mice led to functional recovery. These latter results add further support to the use of systemic IGF-I or its mimetics for treatment of brain injuries.

A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I.

Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency.

A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

Matrix metalloproteinases: new routes to the use of MT1-MMP as a therapeutic target in angiogenesis-related disease.

Angiogenesis, the formation of new vessels from pre-existing capillaries, is a fundamental physiological process which is also critical for the development of several pathological conditions; thus a diminished angiogenic response is related to ischemic disorders, whereas increased angiogenesis is associated with tumorigenesis and chronic inflammatory diseases. New ways of modulating angiogenesis therefore have potential in the treatment of these diseases. During angiogenesis, normally quiescent endothelial cells (ECs) become migratory and invade the surrounding tissue. To do this, they require a specific enzyme machinery to degrade the tissue barriers presented by the basement membranes and the interstitial matrix. This function is supplied by matrix metalloproteinase (MMP) proteins, a large family of enzymes responsible for degrading a variety of extracellular matrix (ECM) components and for modulating the bioactivity of transmembrane receptors and soluble factors. In this review we examine the participation of MMPs--in particular membrane type 1-matrix metalloproteinase (MT1-MMP)--in the different steps of angiogenesis, and discuss the mechanisms of regulation of MT1-MMP in ECs. Finally, we explore the potential use of MMP inhibitors (MMPI) in the treatment of angiogenesis-related disease, with especial emphasis on novel approaches to the inhibition of MT1-MMP activity in ECs.

Tau hyperphosphorylation in apolipoprotein E-deficient and control mice after closed head injury.

Apolipoprotein E (apoE)-deficient mice have learning and memory impairments that are associated with specific neurochemical changes and hyperphosphorylation of distinct epitopes of the cytoskeletal protein tau. Furthermore, such mice are highly susceptible to the sequelae of brain trauma and their ability to recover from head injury is impaired. In the present study we investigated the extent that the neuronal maintenance and repair impairments of apoE-deficient mice are related to aberrations at the tau phosphorylation level. This was pursued by subjecting control and apoE-deficient mice to closed head injury (CHI) and examination, utilizing immunoblot assays, of the resulting effects on tau phosphorylation. The results thus obtained revealed that tau of apoE-deficient mice is hyperphosphorylated before CHI and that this insult results in transient tau hyperphosphorylation, whose extent and time course in the two mouse groups varied markedly. Tau hyperphosphorylation in the injured controls was maximal by about 4 hr after injury and reverted to basal levels by 24 hr. In contrast, almost no head injury-induced tau hyperphosphorylation was observed in the apoE-deficient mice at 4 hr after injury. Some tau hyper-phosphorylation was detected in the head-injured apoE-deficient mice after longer time intervals, but its extent was markedly lower than the maximal values obtained in the head injured controls. These findings show that the chronic neuronal impairments brought about by apoE deficiency and the acute response to head injury are both associated with hyperphosphorylation of the same tau domain and that the ability of apoE-deficient mice to mount the acute tau hyperphosphorylation response to head injury is impaired.

Protein and colloid osmotic pressure changes with albumin and/or saline replacement during plasma exchange.

Colloid osmotic pressure (COP) has been used as a predictor of fluid egress from the vascular space and edema development in the lungs and elsewhere. We investigated the relative safety, as predicted by the COP, of 5 percent albumin plus saline and 5 percent albumin alone as replacement fluids during plasma exchange. Fifty-three one and one-half plasma volume exchanges were performed in 15 patients with a variety of diagnoses using intermittent flow cell separators. On specimens obtained, before, during, and after each plasma exchange, the COP was measured directly with a membrane oncometer , and total protein, albumin, and protein electrophoresis were determined using standard biochemical techniques. COP dropped significantly with one to one 5 percent albumin replacement but even more with one-half 5 percent albumin and one-half saline replacement during the exchange. COP did not fall below 12.5 torr at the end of the plasma exchange, even with one-half saline replacement, compared to the 10 to 12 torr level at which pulmonary edema might be expected. The fall in COP during exchange when saline was given first did approach this range but rapidly reversed itself with albumin administration. Clinically, no evidence of tissue or pulmonary edema was observed. Recovery in total protein and COP between plasma exchanges was significant.