Late-adolescent risk factors for suicide and self-harm in middle-aged men: explorative prospective population-based study.

BACKGROUND: Recent reports show alarmingly high rates of suicide in middle-aged men, yet there are few long-term prospective studies that focus on suicidal behaviour in men in this age group. AIMS: To prospectively explore associations of potential risk factors at age 18 with suicide and self-harm in middle-aged men. METHOD: A population-based Swedish longitudinal cohort study of male conscripts with no history of self-harm at enlistment in 1968-1989 (n = 987 583). Conscription examinations included measures of cognitive performance, stress resilience, psychiatric diagnoses, body mass index (BMI), cardiovascular fitness and muscle strength. Suicides and self-harm at age 45-65 years were identified in the National Hospital Register and Swedish Cause of Death Register. Risks were calculated using Cox proportional hazards models. RESULTS: Low stress resilience (cause-specific hazard ratio CHR = 2.31, 95% CI 1.95-2.74), low cognitive ability (CHR = 2.01, 95% CI 1.71-2.37) as well as psychiatric disorders and low cardiovascular fitness in late adolescence were associated with increased risk for suicide in middle-aged men. Similar risk estimates were obtained for self-harm. In addition, high and low BMI as well as low muscle strength were associated with increased risk of self-harm. Associations also remained significant after exclusion of men with self-harm before age 45. CONCLUSIONS: This prospective study provides life-course perspective support that psychological and physical characteristics in late adolescence may have long-lasting consequences for suicidal behaviour in middle-aged men, a very large population at heightened risk of suicide.

Effects of peripheral administration of GH and IGF-I on gene expression in the hippocampus of hypophysectomised rats.

OBJECTIVE: Growth hormone (GH) increases insulin-like growth factor I (IGF-I) production and both hormones affect hippocampal plasticity. We have previously shown that Hbb and Alas2 in the rat hippocampus were robustly regulated by GH-infusions for six days, whereas other transcripts were weakly affected. Here, we explored the effects of prolonged GH administration on transcripts linked to neuroprotection and investigated whether serum IGF-I administration may exert similar effects. DESIGN: Hypophysectomised female rats were infused with GH or IGF-I for 19 days. Hbb, Alas2 and seven additional GH- and IGF-I-related transcripts were quantified by Q-RT-PCR in rat hippocampus. RESULTS: Three transcripts, Hbb, Alas2, and Alox15 were increased by both GH and IGF-I administration. The other transcripts were marginally affected. CONCLUSION: The 19-day GH-infusion induced similar effects as those reported after 6-day GH treatment, with the addition of the regulation of transcript Alox15. IGF-I induced altered gene expression in relation to its effect on weight gain. This study underlines that there is an entity of transcripts involved in neuroprotection and vascular tone that is regulated by both systemic GH and IGF-I. For other transcripts, the longer duration of this study did not significantly enhance the marginal effects of GH administration seen previously.

Mode of GH administration and gene expression in the female rat brain.

The endogenous secretion of growth hormone (GH) is sexually dimorphic in rats with females having a more even and males a more pulsatile secretion and low trough levels. The mode of GH administration, mimicking the sexually dimorphic secretion, has different systemic effects. In the brains of male rats, we have previously found that the mode of GH administration differently affects neuron-haemoglobin beta (Hbb) expression whereas effects on other transcripts were moderate. The different modes of GH administration could have different effects on brain transcripts in female rats. Hypophysectomised female rats were given GH either as injections twice daily or as continuous infusion and GH-responsive transcripts were assessed by quantitative reverse transcription polymerase chain reaction in the hippocampus and parietal cortex (cortex). The different modes of GH-administration markedly increased Hbb and 5'-aminolevulinate synthase 2 (Alas2) in both brain regions. As other effects were relatively moderate, a mixed model analysis (MMA) was used to investigate general effects of the treatments. In the hippocampus, MMA showed that GH-infusion suppressed glia- and neuron-related transcript expression levels, whereas GH-injections increased expression levels. In the cortex, GH-infusion instead increased neuron-related transcripts, whereas GH-injections had no significant effect. Interestingly, this contrasts to previous results obtained from male rat cortex where GH-infusion generally decreased expression levels. In conclusion, the results indicate that there is a small but significant difference in response to mode of GH administration in the hippocampus as compared to the cortex. For both modes of GH administration, there was a robust effect on Hbb and Alas2.

Nonpsychotic Mental Disorders in Teenage Males and Risk of Early Stroke: A Population-Based Study.

BACKGROUND AND PURPOSE: Although the incidence of stroke is on the decline worldwide, this is not the case for early stroke. We aimed to determine whether nonpsychotic mental disorder at the age of 18 years is a risk factor for early stroke, and if adolescent cardiovascular fitness and intelligence quotient might attenuate the risk. METHOD: Population-based Swedish cohort study of conscripts (n=1 163 845) who enlisted during 1968 to 2005. At conscription, 45 064 males were diagnosed with nonpsychotic mental disorder. Risk of stroke during follow-up (5-42 years) was calculated with Cox proportional hazards models. Objective baseline measures of fitness and cognition were included in the models in a second set of analyses. RESULTS: There were 7770 first-time stroke events. In adjusted models, increased risk for stroke was observed in men diagnosed with depressive/neurotic disorders (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.11-1.37), personality disorders (HR, 1.52; 95% CI, 1.29-1.78), and alcohol/substance use disorders (HR, 1.61; 95% CI, 1.41-1.83) at conscription. Corresponding figures for fatal stroke were HR, 1.38; 95% CI, 1.06 to 1.79; HR, 2.26; 95% CI, 1.60 to 3.19; and HR, 2.20; 95% CI, 1.63 to 2.96. HRs for stroke were attenuated when fitness level and intelligence quotient were introduced. Associations remained significant for personality disorders and alcohol/substance use in the fully adjusted models. The interaction term was statistically significant for fitness but not for intelligence quotient. CONCLUSIONS: Our findings suggest that fitness may modify associations between nonpsychotic disorders and stroke. It remains to be clarified whether interventions designed to improve fitness in mentally ill youth can influence future risk of early stroke.

Influence of Cardiovascular Fitness and Muscle Strength in Early Adulthood on Long-Term Risk of Stroke in Swedish Men.

BACKGROUND AND PURPOSE: Low cardiovascular fitness (fitness) in mid- and late life is a risk factor for stroke. However, the respective effects on long-term stroke risk of fitness and muscle strength in early adulthood are unknown. Therefore, we analyzed these in a large cohort of young men. METHOD: We performed a population-based longitudinal cohort study of Swedish male conscripts registered in 1968 to 2005. Data on fitness (by the cycle ergometric test; n=1 166 035) and muscle strength (n=1,563,750) were trichotomized (low, medium, and high). During a 42-year follow-up, risk of stroke (subarachnoidal hemorrhage, intracerebral hemorrhage, and ischemic stroke) and fatality were calculated with Cox proportional hazards models. To identify cases, we used the International Classification of Diseases-Eighth to Tenth Revision in the Hospital Discharge Register and the Cause of Death Register. RESULTS: First-time stroke events were identified (subarachnoidal hemorrhage, n=895; intracerebral hemorrhage, n=2904; ischemic stroke, n=7767). For all stroke and fatality analysis any type of first-time stroke was recorded (n=10,917). There were inverse relationships in a dose-response fashion between fitness and muscle strength with any stroke (adjusted hazard ratios for the lowest, compared with the highest, tertile of each 1.70 [1.50-1.93] and 1.39 [1.27-1.53], respectively). There were stronger associations for fatal stroke. All 3 stroke types displayed similar associations. Associations between fitness and stroke remained when adjusted for muscle strength, whereas associations between muscle strength and stroke weakened/disappeared when adjusted for fitness. CONCLUSIONS: At the age of 18 years, low fitness and to a lesser degree low muscle strength were independently associated with an increased future stroke risk.

Different modes of GH administration influence gene expression in the male rat brain.

The endogenous secretion pattern in males of GH is episodic in rats and in humans, whereas GH administration is usually even. Different types of GH administration have different effects on body mass, longitudinal bone growth, and liver metabolism in rodents, whereas possible effects on brain plasticity have not been investigated. In this study, GH was administered as a continuous infusion or as two daily injections in hypophysectomized male rats. Thirteen transcripts previously known to respond to GH in the hippocampus and parietal cortex (cortex) were assessed by RT-PCR. To investigate the effects of type of GH administration on several transcripts with different variations, and categories of transcripts (neuron-, glia-, and GH-related), a mixed model analysis was applied. Accordingly, GH injections increased overall transcript abundance more than GH infusions (21% in the hippocampus, P<0.001 and 10% in the cortex, P=0.09). Specifically, GH infusions and injections robustly increased neuronal hemoglobin beta (Hbb) expression significantly (1.8- to 3.6-fold), and GH injections were more effective than GH infusions in increasing Hbb in the cortex (41%, P=0.02), whereas a 23% difference in the hippocampus was not significant. Also cortical connexin 43 was higher in the group with GH injections than in those with GH infusions (26%, P<0.007). Also, there were differences between GH injections and infusions in GH-related transcripts of the cortex (23%, P=0.04) and glia-related transcripts of the hippocampus (15%, P=0.02). Thus, with the exception of Hbb there is a moderate difference in responsiveness to different modes of GH administration.

No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: a population-based cohort study in Sweden.

UNLABELLED: While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. MATERIAL AND METHODS: During 1950-1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. RESULTS: Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.

Cardiovascular and cognitive fitness at age 18 and risk of early-onset dementia.

Patients with early-onset dementia are a significantly under-recognized subgroup of patients with an increasing prevalence. Epidemiological studies are limited and studies of modifiable risk factors, such as physical fitness, are lacking. We aimed to investigate the associations between cardiovascular fitness individually and in combination with cognitive performance at age 18 and risk of early-onset dementia and mild cognitive impairment later in life. We performed a population-based cohort study of over 1.1 million Swedish, 18-year-old, male conscripts, who underwent conscription exams between 1968 and 2005. These males were then followed for up to 42 years. Objective data on cardiovascular fitness and cognitive performance were collected during conscription exams and were subsequently linked with hospital registries to calculate later risk of early-onset dementia and mild cognitive impairment using Cox proportional hazards models controlling for several confounders. The scores from the exams were divided into tertiles (low, medium, high) for the analyses. The mean follow-up time for the analyses was 25.7 years (standard deviation: 9.3) and the median was 27 years. In total, 30 195 315 person-years of follow-up were included in the study. In fully adjusted models, both low cardiovascular fitness and cognitive performance (compared to high) at age 18 were associated with increased risk for future early-onset dementia (cardiovascular fitness, n = 662 events: hazard ratio 2.49, 95%, confidence interval 1.87-3.32; cognitive performance, n = 657 events: hazard ratio 4.11, 95%, confidence interval 3.19-5.29) and mild cognitive impairment (cardiovascular fitness, n = 213 events: hazard ratio 3.57, 95%, confidence interval 2.23-5.74; cognitive performance, n = 212 events: hazard ratio 3.23, 95%, confidence interval 2.12-4.95). Poor performance on both cardiovascular fitness and cognitive tests was associated with a >7-fold (hazard ratio 7.34, 95%, confidence interval 5.08-10.58) and a >8-fold (hazard ratio 8.44, 95%, confidence interval 4.64-15.37) increased risk of early-onset dementia and early-onset mild cognitive impairment, respectively. In conclusion, lower cardiovascular fitness and cognitive performance in early adulthood were associated with an increased risk of early-onset dementia and mild cognitive impairment later in life, and the greatest risks were observed for individuals with a combination of low cardiovascular fitness and low cognitive performance.

Cardiovascular fitness and later risk of epilepsy: a Swedish population-based cohort study.

OBJECTIVE: To analyze the associations between cardiovascular fitness at age 18 years and future risk of epilepsy. METHODS: Population-based cohort study of Swedish male conscripts (n = 1,173,079) born in 1950-1987, who were followed for up to 40 years. Data on cardiovascular fitness were collected during conscription exams and linked with hospital registers to calculate later risk of epilepsy using Cox proportional hazard models controlling for several confounders, including familial factors. RESULTS: Epilepsy was recorded in 6,796 individuals during the follow-up time. In fully adjusted models, low and medium cardiovascular fitness (compared with high) at age 18 years was associated with increased risk of future epilepsy (hazard ratio 1.79, 95% confidence interval 1.57-2.03; and hazard ratio 1.36, 95% confidence interval 1.27-1.45, respectively). The associations changed only marginally after adjustment for familial influences and prior severe traumatic brain injury, cerebrovascular disease, or diabetes. CONCLUSIONS: Low cardiovascular fitness early in life is associated with an increased risk of epilepsy later in adulthood. These results agree with previous results from animal models. We propose that behaviors that increase cardiovascular fitness may act as positive disease-modifiers for the development of epilepsy.

Cardiovascular fitness in males at age 18 and risk of serious depression in adulthood: Swedish prospective population-based study.

BACKGROUND: Studies suggest a role for cardiovascular fitness in the prevention of affective disorders. AIMS: To determine whether cardiovascular fitness at age 18 is associated with future risk of serious affective illness. METHOD: Population-based Swedish cohort study of male conscripts (n = 1 117 292) born in 1950-1987 with no history of mental illness who were followed for 3-40 years. Data on cardiovascular fitness at conscription were linked with national hospital registers to calculate future risk of depression (requiring in-patient care) and bipolar disorder. RESULTS: In fully adjusted models low cardiovascular fitness was associated with increased risk for serious depression (hazard ratios (HR) = 1.96, 95%, CI 1.71-2.23). No such association could be shown for bipolar disorder (HR = 1.11, 95% CI 0.84-1.47). CONCLUSIONS: Lower cardiovascular fitness at age 18 was associated with increased risk of serious depression in adulthood. These results strengthen the theory of a cardiovascular contribution to the aetiology of depression.

Cardiovascular fitness is associated with cognition in young adulthood.

During early adulthood, a phase in which the central nervous system displays considerable plasticity and in which important cognitive traits are shaped, the effects of exercise on cognition remain poorly understood. We performed a cohort study of all Swedish men born in 1950 through 1976 who were enlisted for military service at age 18 (N = 1,221,727). Of these, 268,496 were full-sibling pairs, 3,147 twin pairs, and 1,432 monozygotic twin pairs. Physical fitness and intelligence performance data were collected during conscription examinations and linked with other national databases for information on school achievement, socioeconomic status, and sibship. Relationships between cardiovascular fitness and intelligence at age 18 were evaluated by linear models in the total cohort and in subgroups of full-sibling pairs and twin pairs. Cardiovascular fitness, as measured by ergometer cycling, positively associated with intelligence after adjusting for relevant confounders (regression coefficient b = 0.172; 95% CI, 0.168-0.176). Similar results were obtained within monozygotic twin pairs. In contrast, muscle strength was not associated with cognitive performance. Cross-twin cross-trait analyses showed that the associations were primarily explained by individual specific, non-shared environmental influences (> or = 80%), whereas heritability explained < 15% of covariation. Cardiovascular fitness changes between age 15 and 18 y predicted cognitive performance at 18 y. Cox proportional-hazards models showed that cardiovascular fitness at age 18 y predicted educational achievements later in life. These data substantiate that physical exercise could be an important instrument for public health initiatives to optimize educational achievements, cognitive performance, as well as disease prevention at the society level.

Peripheral administration of GH induces cell proliferation in the brain of adult hypophysectomized rats.

IGF-I treatment has been shown to enhance cell genesis in the brains of adult GH- and IGF-I-deficient rodents; however, the influence of GH therapy remains poorly understood. The present study investigated the effects of peripheral recombinant bovine GH (bGH) on cellular proliferation and survival in the neurogenic regions (subventricular zone (SVZ), and dentate gyrus of the hippocampus), as well as the corpus callosum, striatum, parietal cortex, and piriform cortex. Hypopituitarism was induced in female rats by hypophysectomy, and the rats were supplemented with thyroxine and cortisone acetate. Subsequently, the rats received daily s.c. injections of bGH for either 6 or 28 days respectively. Following 5 days of peripheral bGH administration, the number of bromodeoxyuridine (BrdU)-positive cells was increased in the hippocampus, striatum, parietal cortex, and piriform cortex after 6 and 28 days. In the SVZ, however, BrdU-positive cells increased only after 28 days of bGH treatment. No significant change was observed in the corpus callosum. In the hippocampus, after 28 days of bGH treatment, the number of BrdU/NeuN-positive cells was increased proportionally to increase the number of BrdU-positive cells. (3)H-thymidine incorporation in vitro revealed that 24 h of bGH exposure was sufficient to increase cell proliferation in adult hippocampal progenitor cells. This study shows for the first time that 1) peripheral bGH treatment increased the number of newborn cells in the adult brain and 2) bGH exerted a direct proliferative effect on neuronal progenitor cells in vitro.

Proliferative and protective effects of growth hormone secretagogues on adult rat hippocampal progenitor cells.

Progenitor cells in the subgranular zone of the hippocampus may be of significance for functional recovery after various injuries because they have a regenerative potential to form new neuronal cells. The hippocampus has been shown to express the GH secretagogue (GHS) receptor 1a, and recent studies suggest GHS to both promote neurogenesis and have neuroprotective effects. The aim of the present study was to investigate whether GHS could stimulate cellular proliferation and exert cell protective effects in adult rat hippocampal progenitor (AHP) cells. Both hexarelin and ghrelin stimulated increased incorporation of (3)H-thymidine, indicating an increased cell proliferation. Furthermore, hexarelin, but not ghrelin, showed protection against growth factor deprivation-induced apoptosis, as measured by annexin V binding and caspase-3 activity and also against necrosis, as measured by lactate dehydrogenase release. Hexarelin activated the MAPK and the phosphatidylinositol 3-kinase/Akt pathways, whereas ghrelin activated only the MAPK pathway. AHP cells did not express the GHS receptor 1a, but binding studies could show specific binding of both hexarelin and ghrelin, suggesting effects to be mediated by an alternative GHS receptor subtype. In conclusion, our results suggest a differential effect of hexarelin and ghrelin in AHP cells. We have demonstrated stimulation of (3)H-thymidine incorporation with both hexarelin and ghrelin. Hexarelin, but not ghrelin, also showed a significant inhibition of apoptosis and necrosis. These results suggest a novel cell protective and proliferative role for GHS in the central nervous system.

Peripheral infusion of insulin-like growth factor-I increases the number of newborn oligodendrocytes in the cerebral cortex of adult hypophysectomized rats.

We have previously shown that recombinant human (rh) IGF-I induces cell proliferation and neurogenesis in the hippocampus of hypophysectomized rats. In the current investigation, we determined the effects of rhIGF-I on proliferation and differentiation in the cerebral cortex. Adult hypophysectomized rats were injected with bromodeoxyuridine (BrdU) to label newborn cells (once a day for the first 5 d), and rhIGF-I was administered peripherally for 6 or 20 d. In the cerebral cortex, the number of BrdU-labeled cells increased after 20 d but not after 6 d of rhIGF-I infusion. This suggests that rhIGF-I enhances the survival of newborn cells in the cerebral cortex. Using BrdU labeling combined with the oligodendrocyte-specific markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase, we demonstrated an increase in oligodendrogenesis in the cerebral cortex. The total amount of myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase was also increased on Western blots of homogenates of the cerebral cortex, confirming the immunohistochemical findings. Also, we observed an increase in the number of capillary-associated BrdU-positive cells, although total capillary area was not increased. rhIGF-I treatment did not affect cortical astrogliogenesis and neurogenesis was not observed. The ability of rhIGF-I to induce cortical oligodendrogenesis may have implications for the regenerative potential of the cortex.

Interaction of scavenger receptor class B type I with peroxisomal targeting receptor Pex5p.

Scavenger receptor class B type I (SR-BI) is an HDL receptor that mediates selective HDL lipid uptake. Peroxisomes play an important role in lipid metabolism and peroxisomal targeting signal type 1 (PTS1)-containing proteins are translocated to peroxisomes by the peroxisomal targeting import receptor, Pex5p. We have previously identified a PTS1 motif in the intracellular domain of rat SR-BI. Here, we examine the possible interaction between Pex5p and SR-BI. Expression of a Flag-tagged intracellular domain of SR-BI resulted in translocation to the peroxisome as demonstrated by double labeling with anti-Flag IgG and anti-catalase IgG analyzed by confocal microscopy. Immunoprecipitation experiments with anti-SR-BI antibody showed that Pex5p co-precipitated with SR-BI. However, when an antibody against Pex5p was used for immunoprecipitation, only the 57kDa, non-glycosylated form, of SR-BI co-precipitated. We conclude that the PTS1 domain of SR-BI is functional and can mediate peroxisomal interaction via Pex5p, in vitro.

IGF-I has a direct proliferative effect in adult hippocampal progenitor cells.

The aim of the present study was to investigate the potential direct effects of insulin-like growth factor-I (IGF-I) on adult rat hippocampal stem/progenitor cells (AHPs). IGF-I-treated cultures showed a dose-dependent increase in thymidine incorporation, total number of cells, and number of cells entering the mitosis phase. Pretreatment with fibroblast growth factor-2 (FGF-2) increased the IGF-I receptor (IGF-IR) expression, and both FGF-2 and IGF-I were required for maximal proliferation. Time-lapse recordings showed that IGF-I at 100 ng/ml decreased differentiation and increased proliferation of single AHPs. Specific inhibition of mitogen-activated protein kinase kinase (MAPKK), phosphatidylinositol 3-kinase (PI3-K), or the downstream effector of the PI3-K pathway, serine/threonine p70 S6 kinase (p70(S6K)), showed that both the MAPK and the PI3-K pathways participate in IGF-I-induced proliferation but that the MAPK activation is obligatory. These results were confirmed with dominant-negative constructs for these pathways. Stimulation of differentiation was found at a low dose (1 ng/ml) of IGF-I, clonal analysis indicating an instructive component of IGF-I signaling.

Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitro.

Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I--at which stimulation of proliferation occurred--did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism.

Insulin-like growth factor-I and neurogenesis in the adult mammalian brain.

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.