Endothelial dysfunction and cardiovascular disease: the role of predictive adaptive responses.
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Adaptation, Physiological↗
Biomedical subjects
P Gluckman
Publications and source records attributed to P Gluckman.
N-terminal tripeptide of IGF-1 improves functional deficits after 6-OHDA lesion in rats.
Central administration of N-terminal tripeptide of IGF-1 (GPE) prevents the loss of dopamine neurons. We now examine effects of GPE administered peripherally, on long-term functional recovery after 6-OHDA lesion in rats. GPE treatment (3 mg/kg, i.p.), 3 days after the lesion reduced the number of rotations (p<0.005) and the time over meter (p<0.005) compared to vehicle treatment. Step length and number of adjusting steps were increased in the GPE group (p<0.005), particularly at 12 weeks post lesion. However, GPE treatment did not prevent the loss of tyrosine hydroxylase in the substantia nigra pars compacta and the striatum. The study suggests that peripheral administration of GPE after onset of nigrostriatal dopamine depletion improves long-term Parkinsonian motor deficits, independent of neuronal outcome.
Animals↗
The metabolic effects of short-term administration of physiological versus high doses of GH therapy in GH deficient adults.
OBJECTIVE: GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI). The short-term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short-term administration of two 'physiological' ('lowest' dose: 0.0017 mg/kg/day; 'low' dose: 0.0033 mg/kg/day) with two 'supraphy-siological' ('high' dose: 0.010 mg/kg/day; 'highest' dose: 0.025 mg/kg/day) GH doses on SI, beta-cell function, IGF-1 and IGFBPs -1 and -3 in a group of GHD adults. PATIENTS AND METHODS: Thirteen GHD adults were recruited (seven men, aged 23-63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7-day treatment phase. Fasting blood samples were collected daily (days 1-8), and SI and beta-cell function were calculated using the homeostasis model assessment (HOMA). RESULTS: All four GH doses increased IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio, and decreased IGFBP-1 from day 3 onwards (P < 0.05). The highest dose increased fasting glucose (P < 0.001), insulin (P < 0.001) and beta-cell function (P < 0.001), but decreased SI (P < 0.001). The high and low doses did not modify fasting glucose and insulin, SI or beta-cell function, whereas the lowest dose enhanced beta-cell function (P < 0.05). The overall increase in the GH dose increased IGF-1, IGFBP-3, fasting glucose and insulin (P < 0.001), demonstrated a positive correlation with the final change in fasting glucose (r = 0.5, P < 0.05) and insulin (r = 0.8, P < 0.001) and a negative correlation with final SI (r = -0.5, P < 0.05). CONCLUSIONS: Our results suggest that short-term administration of the highest GH dose induced insulin resistance, whereas the lowest dose (0.0017 mg/kg/day) could represent the optimal starting dose in GHD adults due to its beneficial effects on beta-cell function without compromising SI. It is, however, yet to be determined whether the positive effects of the lowest GH dose on beta-cell function can be demonstrated over a longer period of time.
Adult↗
Glucose tolerance in adults after prenatal exposure to famine.
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Animals↗
Angiolymphoid hyperplasia with eosinophilia of the parotid gland.
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Adult↗
N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats.
The effect of the N-terminal tripeptide of insulin-like growth factor (IGF)-1, glycine-proline-glutamate (GPE), as a neuroprotective agent for nigro-striatal dopaminergic neurons was examined in the present study using a rat model of Parkinson's disease. A unilateral nigro-striatal lesion was induced in rats by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). GPE (3 microgram) or its vehicle was administered intracerebroventricularly (i.c.v.) 2 h after the 6-OHDA lesion. Tyrosine-hydroxylase (TH) immunohistochemistry in the substantia nigra compacta (SNc) and the striatum were examined 2 weeks after the lesion. Following 6-OHDA injection, the number of TH immunopositive neurons in the ipsilateral SNc was reduced. The density of TH immunostaining was also reduced in the ipsilateral SNc and the striatum. Treatment with a single dose of GPE (n=9) significantly prevented the loss of TH immunopositive neurons (p<0. 001) and restored the TH immunoreactivity in both the SNc and the striatum compared with the vehicle control group (n=9, p<0.001). The results suggest that GPE showed promise as a potential treatment for Parkinson's disease.
Animals↗
Neuronal death and survival in two models of hypoxic-ischemic brain damage.
Two unilateral hypoxic-ischemia (HI) models (moderate and severe) in immature rat brain have been used to investigate the role of various transcription factors and related proteins in delayed neuronal death and survival. The moderate HI model results in an apoptotic-like neuronal death in selectively vulnerable regions of the brain while the more severe HI injury consistently produces widespread necrosis resulting in infarction, with some necrosis resistant cell populations showing evidence of an apoptotic type death. In susceptible regions undergoing an apoptotic-like death there was not only a prolonged induction of the immediate early genes, c-jun, c-fos and nur77, but also of possible target genes amyloid precursor protein (APP751) and CPP32. In contrast, increased levels of BDNF, phosphorylated CREB and PGHS-2 were found in cells resistant to the moderate HI insult suggesting that these proteins either alone or in combination may be of importance in the process of neuroprotection. An additional feature of both the moderate and severe brain insults was the rapid activation and/or proliferation of glial cells (microglia and astrocytes) in and around the site of damage. The glial response following HI was associated with an upregulation of both the CCAAT-enhancer binding protein alpha (microglia only) and NFkappaB transcription factors.
Animals↗
ATF-2 phosphorylation in apoptotic neuronal death.
Activating transcription factor (ATF-2) is a basic region-leucine zipper transcription factor that can mediate a diverse range of transcriptional responses including those generated by various forms of cellular stress. Activation of ATF-2 in response to these stimuli requires post-translational modification, in particular the phosphorylation of Thr69 and Thr71. To investigate whether ATF-2 activation also has a role in neuronal apoptosis, immunocytochemistry using a phospho-specific ATF-2 (Thr71) antibody was carried out in the 21 day old rat brain following a unilateral hypoxic-ischemic (HI) insult and PC12 cells cultured in the presence of okadaic acid. In both models a dramatic increase in phosphorylated ATF-2 was found within cells undergoing apoptosis.
Activating Transcription Factor 2↗
CCAAT-enhancer binding protein alpha is expressed in activated microglial cells after brain injury.
Microglial cells play important roles in brain injury and repair and are implicated in diseases such as Alzheimer's disease, Creutzfeldt-Jacob disease, multiple sclerosis, the Aids Dementia Complex and stroke. Despite their importance in neuropathology, the underlying molecular basis for the activation of microglia after brain injury is not understood. We show, using RT-PCR, in situ hybridisation, immunocytochemistry, and electrophoretic mobility shift assay, that the CCAAT-enhancer binding protein alpha (C/EBP alpha), a sequence specific DNA-binding protein, is induced in microglial cells, but not astrocytes or neurons, after hypoxic-ischemic brain injury. These results suggest that C/EBP alpha might regulate gene expression and consequentially have a role in the activation and/or proliferation of microglia following brain injury.
Animals↗
Do c-Jun, c-Fos, and amyloid precursor protein play a role in neuronal death or survival?
A unilateral hypoxic-ischemic (HI) episode in immature rat brain was used to investigate the role of the immediate early genes c-fos and c-jun in delayed neuronal death and survival. This HI paradigm results in an apoptotic cell death in selectively vulnerable areas, in particular the hippocampal CA1 pyramidal cell layer. In susceptible regions undergoing delayed neuronal death there was a prolonged induction of both c-Jun and c-Fos (mRNA and protein). This expression occurred in parallel with a pronounced increase in AP-1 DNA binding activity but was not associated with either increased levels of Jun NH2-terminal kinase or phosphorylation of c-Jun (ser-63). In addition to changes in immediate early gene expression, the CA1 neurons showed a delayed increase in the expression of amyloid precursor protein (APP751) mRNA, suggesting that APP, which contains an AP-1 site, might be a down-stream gene regulated by the Jun transcription factor in neurons dying by apoptosis. The surviving dentate granule cells also showed an increase in Fos, Jun, and APP751 although this expression occurred earlier than in the CA1 neurons and declined rapidly. These results are discussed with respect to the role of these proteins in neuronal death and survival.
Amyloid beta-Protein Precursor↗
Metastatic testicular teratoma of the nasal cavity: a rare cause of severe intractable epistaxis.
Malignant neoplasms of the nasal cavity and paranasal sinuses are uncommon. Choriocarcinoma is a highly malignant germ cell tumour occurring in the reproductive organs. Metastasis may be principally by the lymphatic route as in other germ cell tumours but choriocarcinoma is also known to spread haematogenously. We present a rare case of metastatic choriocarcinoma to the nasal cavity from testicular teratoma presenting with intractable epistaxis in a 32-year-old Caucasian male, who ultimately succumbed to this disease.
Adult↗
Maturational change in the cortical response to hypoperfusion injury in the fetal sheep.
A characteristic of perinatal encephalopathies are the distinct patterns of neuronal and glial cell loss. Cerebral hypoperfusion is thought to be a major cause of these lesions. Gestational age is likely to influence outcome. This study compares the cortical electrophysiologic and histopathologic responses to hypoperfusion injury between preterm and near term fetuses. Chronically instrumented 0.65 (93-99-d, n = 9) and 0.9 (119-133-d, n = 6) gestation fetal sheep underwent 30 min of cerebral hypoperfusion injury. The parasagittal cortical EEG and impedance (measure of cytotoxic edema) responses plus histologic outcome (3 d) were compared. The acute rise in impedance was similar in amplitude, but the onset was delayed (5.0 +/- 0.7 versus 9.1 +/- 1.1 min, p < 0.05) in the preterm fetuses relative to those near term. In contrast the extent of the secondary rise was reduced (p < 0.01) and peaked earlier in the preterm fetuses (19.8 +/- 1.0 versus 40.5 +/- 3.5 h, p < 0.01). Both groups had a similar fall in EEG spectral edge frequency. The preterm fetuses had a milder loss of EEG intensity at 72 h (-7.7 +/- 1.5 versus -12.8 +/- 0.9 dB, p < 0.05). At both ages there was a predominantly parasagittal cortical distribution of damage with a similar pattern of neuronal loss in the thalamus and striatum. There was extensive selective neuronal loss within the upper layers of the cortex in those near term. In contrast the preterm fetuses developed subcortical infarcts (p < 0.05). The cortical response to injury altered during the last trimester. The results suggest the severity of the delayed phase of cortical neuronal injury and selective neuronal loss increased near term. In contrast, the preterm fetuses had a more rapidly evolving injury leading to necrosis of the subcortical white matter.
Animals↗
Annexin V labels apoptotic neurons following hypoxia-ischemia.
The translocation of phosphatidylserine from the cytosol to the external surface of the plasma membrane has been documented as a characteristic feature of apoptosis in a number of cell types. Annexin V is a calcium-dependent phospholipid binding protein that has high affinity for phosphatidylserine. To investigate whether Annexin V provides a marker of apoptosis in the central nervous system we carried out histochemical analysis of its binding in the 21-day-old rat brain at various time-points following a moderate unilateral hypoxic-ischemic (HI) insult. The CA1 pyramidal neurons, which are selectively vulnerable to HI injury and that die by an apoptotic mechanism showed an increase in Annexin V binding 48-168 hours post-insult.
Animals↗
Focal brain injury increases activin betaA mRNA expression in hippocampal neurons.
The role of activin in the mammalian brain is of increasing interest as evidence accumulates to suggest a number of different neural functions. Here, we report that activin betaA mRNA is transiently induced in dentate gyrus neurons after unilateral mechanical brain injury by saline injection. Expression is dependent on NMDA receptor activation since pretreatment with MK801 (5 mg/kg, i.p.) largely attenuates the signal. Induction also requires de novo protein synthesis, as cycloheximide (10 mg/kg, i.p.) pretreatment abolishes the expression of activin betaA mRNA 1 h after injury. These results show that activin betaA mRNA expression is regulated by excitatory activity induced by focal brain injury and suggests a possible neuroplastic role in the recovery from such injury.
Animals↗
Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus.
Recent studies indicate that the proto-oncogene Bax, and other related proteins (eg Bcl-2) may play a major role in determining whether cells will undergo apoptosis under conditions which promote cell death. Increased expression of Bax has been found to promote apoptosis, while over-expression of Bcl-2 can inhibit apoptosis. To investigate the role of Bax in nerve cell death in the rat brain we examined the level of Bax expression in cells undergoing apoptosis, using a hypoxic-ischemic stroke model. We found that Bax was expressed at high levels in the nuclei of neurons in the hippocampus, cortex, cerebellum, and striatum on the control side, and that Bax levels increased in hippocampal neurons undergoing apoptosis on the stroke side, and then declined (correlating with cell loss). In the Alzheimer's disease hippocampi we found a concentrated localisation of Bax in senile plaques, which correlated with the localisation of beta-amyloid protein in adjacent sections from the same brains. beta-Amyloid positive plaques are thought to contribute to the Alzheimer's disease process, possibly via an apoptotic mechanism, and this may occur via an increase in Bax in these areas. Bax was also strongly stained in tau-positive tangles in Alzheimer's disease hippocampi, suggesting Bax may play a role in tangle formation. In addition, we observed a loss of Bax expression in the dentate granule cells of Alzheimer's disease hippocampi compared with moderate Bax expression in control hippocampi, and this loss may be related to the survival of these neurons in Alzheimer's disease. Finally, we observed substantially different staining patterns of Bax using three different commercially available antisera to Bax, indicating the need for caution when interpreting results in this area.
Adult↗
Loss of Ref-1 protein expression precedes DNA fragmentation in apoptotic neurons.
Ref-1 is a bifunctional protein that has been implicated in the transcriptional regulation of AP-1 elements and in DNA repair. To investigate whether Ref-1 is involved in programmed cell death its expression was measured in the 21-day-old rat brain at various time-points following a moderate unilateral hypoxic-ischemic (HI) insult. The CA1 pyramidal cells, which are selectively vulnerable to HI injury, showed a significant decrease in Ref-1 immunoreactivity 48 h-7 days post-insult. This loss of Ref-1 immunoreactivity may contribute to a decrease in endogenous repair activity and the development of apoptosis in the CA1 pyramidal cells.
Animals↗
The role of the cyclic AMP-responsive element binding protein (CREB) in hypoxic-ischemic brain damage and repair.
The cyclic AMP-responsive element binding protein (CREB) is a basally expressed, post-translationally activated transcription factor that has been implicated in the trans-activation of a number of genes in response to cAMP and calcium signals. A unilateral hypoxic-ischemic (HI) injury in the 21 day old rat was used to examine a potential role for CREB (phosphorylated and unphosphorylated) in neuronal programmed cell death or cell survival. The selectively vulnerable CAI pyramidal cells, which undergo delayed neuronal death following mild HI, show a loss of CREB and phosphorylated CREB (pCREB) immunoreactivity on the injured side 48 and 72 h following HI. In contrast the resistant dentate granule cells and cortical cells produce a bimodal increase in pCREB immunoreactivity, peaking 6 and 48 h following HI. The fact that cells surviving the HI insult are showing increased activation of CREB suggests that this protein might be involved in the process of neuroprotection.
Animals↗
Induction of clusterin in the immature brain following a hypoxic-ischemic injury.
A unilateral hypoxic-ischemic (HI) insult in the 21 day old rat has been used to assess the role of clusterin in nerve cell death. Both clusterin mRNA and protein levels were measured at various time points after moderate (15 min) and severe (60 min) HI insult using in situ hybridisation and immunocytochemistry respectively. The severe HI insult lead primarily to necrotic neuronal death and showed very little if any clusterin mRNA and protein induction on the ligated side of the brain. However, following the moderate HI insult there was a dramatic time-dependent accumulation of clusterin protein in neurons of the CA1-CA2 pyramidal cell layers in the hippocampus and cortical layers 3-5, regions undergoing delayed neuronal death. Clusterin mRNA expression, in contrast to neuronal protein accumulation, appeared to be glial in origin (probably astrocytes) with increases in mRNA in and around the hippocampal fissure and only a weak signal over the CA1-CA2 pyramidal cell layer. These results support the hypothesis that the clusterin protein is synthesised in the astrocytes, secreted and then taken up by dying neurons. Clusterin immunoreactivity and in situ DNA end-labelling performed on the same sections revealed that clusterin was accumulating in neurons destined to die by programmed cell death. However the relative time-courses of DNA fragmentation and clusterin immunoreactivity suggest that clusterin production was a result of the selective delayed neuronal death rather than being involved in the biochemical cascade of events that cause it.
Animals↗