Increased Glial Fibrillary Acidic Protein Levels Research Articles

Caregiving-Related Depression Increases Neuroinflammation in Spousal Caregivers to Individuals with Cognitive Impairment: A Longitudinal Study

Abstract Background The caregiving burden of the spousal caregivers (SCGs) to individuals with cognitive impairment poses public health challenges with adverse psychosocial and physiological effects. However, few studies have investigated the neurobiological impact of caregiving, particularly through the investigation of neuroinflammation and neurodegeneration. Methods Using data from a longitudinal cohort at Chungnam National University Hospital, the relationship between caregiving burden, neuroinflammation and neurodegeneration was examined in 38 older adult couples over a 16-month period. Caregiving burden was assessed through a multifaceted approach. For factors related to the care recipient, we assessed cognitive function and neuropsychiatric symptoms. Factors regarding the SCGs included the measurement of perceived depression. Glial fibrillary acidic protein (GFAP) was used as a plasma biomarker for neuroinflammation and neurofilament light chain (NfL) for neurodegeneration. Regression analyses were adjusted for age, sex, apolipoprotein E status, follow-up interval, vascular risk factors, and physical activity. Results Changes in depression among SCGs were significantly correlated with increased GFAP levels (p = 0.003), indicating that greater depressive symptoms during caregiving are associated with increased neuroinflammation. In contrast, no significant correlations were found between changes in cognitive function or neuropsychiatric symptoms in care recipients and the plasma biomarker levels of SCGs. Additionally, there was no significant association between changes in depression and NfL levels in SCGs. Conclusions The psychological stress experienced by SCGs while caring for partners with cognitive impairment actively contributes to neuroinflammation, a well-known risk factor for various diseases. This study emphasizes the need to address psychological stress experienced by older adult caregivers.

Glial Fibrillary Acidic Protein Levels in Post-Stroke Depression: A Prospective Ischemic Stroke Cohort.

Increased glial fibrillary acidic protein (GFAP) levels were found in cerebrovascular disease patients. The pathogenesis of depression after ischemic stroke remains largely unknown. Here, we aim to determine whether GFAP concentrations were associated with post-stroke depression (PSD) at 3 months. From March 2022 to September 2022, patients with first-ever ischemic stroke were prospectively recruited. GFAP concentrations were detected within 24 h using an enzyme-linked immunosorbent assay. The PSD was defined as a Hamilton Depression Rating Scale 24-Item score ≥ 8. A total of 206 subjects with ischemic stroke (mean age: 63.6 years; 49.0% female) were enrolled. During the 90-day follow-up, 57 participants (27.7%) were observed in PSD. The median serum GFAP concentrations were 0.67 ng/mL. After adjustment for the covariates, higher increased GFAP levels were associated with increased risk of PSD (odds ratio [OR], 7.12; 95% confidence interval [CI], 3.29-15.44; P < 0.001). Also, the multivariate-adjusted OR of PSD associated with the fourth quartile of GFAP was 10.89 (95% CI, 3.53-33.60; P < 0.001) compared with the first quartile. Furthermore, the restricted cubic spline confirmed a linear association between GFAP and the risk of PSD (P for linearity < 0.001). Our results indicated that increased circulating GFAP concentrations were significantly correlated with the risk of PSD at 3 months. Measuring the GFAP levels after ischemic stroke may add some values for the risk stratifying of PSD.

Extracellular vesicles released after cranial radiation: An insight into an early mechanism of brain injury

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) protein-bound 4-hydroxy-2-nonenal (HNE) adducts, an oxidative damage marker. Brain tissues were prepared for immunohistochemistry staining and protein immunoblotting. The results demonstrate: 1) increased GFAP levels (p < 0.05) in EVs, but not brain tissue, in the IR group; and 2) increased HNE-bound protein adduction levels (p < 0.05). The results support using EVs as an early indicator of cancer therapy-induced neuronal injury.

Sigma 1 Receptor Modulates Optic Nerve Head Astrocyte Reactivity.

PurposeStimulation of Sigma 1 Receptor (S1R) is neuroprotective in retina and optic nerve. S1R is expressed in both neurons and glia. The purpose of this work is to evaluate the ability of S1R to modulate reactivity responses of optic nerve head astrocytes (ONHAs) by investigating the extent to which S1R activation alters ONHA reactivity under conditions of ischemic cellular stress.MethodsWild type (WT) and S1R knockout (KO) ONHAs were derived and treated with vehicle or S1R agonist, (+)-pentazocine ((+)-PTZ). Cells were subjected to six hours of oxygen glucose deprivation (OGD) followed by 18 hours of re-oxygenation (OGD/R). Astrocyte reactivity responses were measured. Molecules that regulate ONHA reactivity, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-kB), were evaluated.ResultsBaseline glial fibrillary acidic protein (GFAP) levels were increased in nonstressed KO ONHAs compared with WT cultures. Baseline cellular migration was also increased in nonstressed KO ONHAs compared with WT. Treatment with (+)-PTZ increased cellular migration in nonstressed WT ONHAs but not in KO ONHAs. Exposure of both WT and KO ONHAs to ischemia (OGD/R), increased GFAP levels and cellular proliferation. However, (+)-PTZ treatment of OGD/R-exposed ONHAs enhanced GFAP levels, cellular proliferation, and cellular migration in WT but not KO cultures. The (+)-PTZ treatment of WT ONHAs also enhanced the OGD/R-induced increase in cellular pSTAT3 levels. However, treatment of WT ONHAs with (+)-PTZ abrogated the OGD/R-induced rise in NF-kB(p65) activation.ConclusionsUnder ischemic stress conditions, S1R activation enhanced ONHA reactivity characteristics. Future studies should address effects of these responses on RGC survival.

Increased levels of Aβ42 decrease the lifespan ofob/obmice with dysregulation of microglia and astrocytes

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated AppNL-F/wt knock-in; ob/ob mice by crossing AppNL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. AppNL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, AppNL-F/wt knock-in mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in AppNL-F/wt knock-in mice and AppNL-F/wt knock-in; ob/ob mice at 18months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in AppNL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and AppNL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young AppNL-F/wt knock-in; ob/ob mice. Thus, the increased Aβ42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.

Lestaurtinib (CEP-701) modulates the effects of early life hypoxic seizures on cognitive and emotional behaviors in immature rats

Hypoxic encephalopathy of the newborn is a major cause of long-term neurological sequelae. We have previously shown that CEP-701 (lestaurtinib), a drug with an established safety profile in children, attenuates short-term hyperexcitability and tropomyosin-related kinase B (TrkB) receptor activation in a well-established rat model of early life hypoxic seizures (HS). Here, we investigated the potential long-term neuroprotective effects of a post-HS transient CEP-701 treatment. Following exposure to global hypoxia, 10 day old male Sprague–Dawley pups received CEP-701 or its vehicle and were sequentially subjected to the light–dark box test (LDT), forced swim test (FST), open field test (OFT), Morris water maze (MWM), and the modified active avoidance (MAAV) test between postnatal days 24 and 44 (P24-44). Spontaneous seizure activity was assessed by epidural cortical electroencephalography (EEG) between P50 and 100. Neuronal density and glial fibrillary acidic protein (GFAP) levels were evaluated on histological sections in the hippocampus, amygdala, and prefrontal cortex at P100. Vehicle-treated hypoxic rats exhibited significantly increased immobility in the FST compared with controls, and post-HS CEP-701 administration reversed this HS-induced depressive-like behavior (p < 0.05). In the MAAV test, CEP-701-treated hypoxic rats were slower at learning both context-cued and tone-signaled shock-avoidance behaviors (p < 0.05). All other behavioral outcomes were comparable, and no recurrent seizures, neuronal loss, or increase in GFAP levels were detected in any of the groups. We showed that early life HS predispose to long-lasting depressive-like behaviors, and that these are prevented by CEP-701, likely via TrkB modulation. Future mechanistically more specific studies will further investigate the potential role of TrkB signaling pathway modulation in achieving neuroprotection against neonatal HS, without causing neurodevelopmental adverse effects.

Calcium Dobesilate Is Protective against Inflammation and Oxidative/Nitrosative Stress in the Retina of a Type 1 Diabetic Rat Model

Calcium dobesilate (CaD) has been prescribed to some patients in the early stages of diabetic retinopathy to delay its progression. We previously reported that the treatment of diabetic animals (4 weeks of diabetes) with CaD, during the last 10 days of diabetes, prevents blood-retinal barrier breakdown. Here, we aimed to investigate whether later treatment of diabetic rats with CaD would reverse inflammatory processes in the retina. Diabetes was induced with streptozotocin, and 6 weeks after diabetes onset, CaD (100 mg/kg/day) was administered for 2 weeks. The treatment with CaD significantly increased glial fibrillary acidic protein (GFAP) levels in the retina of nondiabetic animals (138.6 ± 12.8% of control) and enhanced the diabetes-induced increase in GFAP levels (174.8 ± 5.6% of control). In addition, CaD prevented the increase in mRNA and protein expression of tumor necrosis factor and interleukin-1β, as well as the formation of oxidized carbonyl residues and the increase in nitrotyrosine immunoreactivity, particularly in the ganglion cell layer of diabetic animals. We demonstrate that the treatment of diabetic animals with CaD can reverse the established proinflammatory processes in the retina. These beneficial effects appear to be attributed, at least partially, to the antioxidant properties of CaD.

Association of nadir oxygen delivery on cardiopulmonary bypass with serum glial fibrillary acid protein levels in paediatric heart surgery patients.

Protecting the brain during cardiac surgery is a major challenge. We evaluated associations between nadir oxygen delivery (DO2) during paediatric cardiac surgery and a biomarker of brain injury, glial fibrillary acidic protein (GFAP). Blood samples were obtained during a prospective, single-centre observational study of children undergoing congenital heart surgery with cardiopulmonary bypass (CPB) (2010-2011). Remnant blood samples, collected serially prior to cannulation for bypass and until incision closure, were analysed for GFAP levels. Perfusion records were reviewed to calculate nadir DO2. Linear regression analysis was used to assess the association between nadir DO2 and GFAP levels. A total of 116 consecutive children were included, with the median age of 0.75 years (interquartile range: 0.42-8.00) and the median weight of 8.3 kg (5.8-20.0). Single-ventricle anatomy was present in 19 patients (16.4%). Deep hypothermic circulatory arrest (DHCA) was used in 14 patients (12.1%). On univariable analysis, nadir DO2 was significantly associated with GFAP values measured during rewarming on CPB (P = 0.005) and after CPB decannulation (P = 0.02). On multivariable analysis controlling for CPB time, DHCA and procedure risk category, a significant negative relationship remained between nadir DO2 and post-CPB GFAP (P = 0.03). Lower nadir DO2 is associated with increased GFAP levels, suggesting that diminished DO2 during paediatric heart surgery may be contributing to neurological injury. The DO2-GFAP relationship may provide a useful measure for the implementation of neuroprotective strategies in paediatric heart surgery, including goal-directed perfusion.

Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression

Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 ms) is the most effective treatment available for severe depression. However, its use is associated with side-effects. The stimulus in ultrabrief pulse ECT (UBP ECT; pulse width 0.25-0.3 ms) is more physiological and has been reported to be associated with less cognitive side-effects, but its antidepressant effectiveness is not yet well established. Using electroconvulsive stimulation (ECS), the animal model of ECT, we previously reported UBP ECS to be significantly less effective than well-established BP ECS in eliciting behavioural, molecular and cellular antidepressant-related effects in naïve rats. We have now compared the effects of BP and UBP ECS in an animal model of depression related to exogenous supplementation with the stress-induced glucocorticoid hormone, corticosterone. Corticosterone administration resulted in an increase in immobility time in the forced swim test (FST) (p < 0.01) and decreases in the expression of brain-derived neurotrophic factor (BDNF) (p < 0.05) and glial fibrillary acidic protein (GFAP) (p < 0.001) in the hippocampus and frontal cortex. There was no significant difference in the duration or type of seizure induced by BP (0.5 ms) or UBP (0.3 ms) ECS. UBP ECS proved to be as effective as BP ECS at inducing a behavioural antidepressant response in the FST with a significant decrease (p < 0.001) in immobility seen following administration of ECS. Both forms of ECS also induced significant increases in BDNF protein (p < 0.01) expression in the hippocampus. BP ECS (p < 0.05) but not UBP ECS induced a significant increase in GFAP levels in the hippocampus and frontal cortex. Overall, UBP ECS effectively induced antidepressant-related behavioural and molecular responses in the corticosterone supplementation model, providing the first preclinical data on the potential role of this form of ECS to treat a depression phenotype related to elevated corticosterone.

Increased expression of glial fibrillary acidic protein in prefrontal cortex in psychotic illness

Astrocyte dysregulation has been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD), however the exact nature of astrocytic alterations remains to be identified. In this study we investigated whether levels of four astrocyte-specific proteins; glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase 1L1 (ALDH1L1), vimentin and excitatory amino acid transporter 1 (EAAT1) are altered in SCZ and BPD. Relative concentrations of GFAP, ALDH1L1, vimentin and EAAT1 were assessed post-mortem in dorsolateral prefrontal cortex in SCZ (n=35), BPD (n=34) and non-psychiatric controls (n=35) by western blotting. The same proteins were also quantified in cingulate cortex of rats administered the antipsychotics haloperidol and clozapine. Elevated levels of GFAP were observed in SCZ and BPD, when compared to controls. GFAP was also significantly increased when comparing individuals with psychotic symptoms against those without. Vimentin, ALDH1L1 and EAAT1 levels did not differ between groups. Rats exposed to antipsychotics did not exhibit significant differences in any astrocytic protein, suggesting that increased GFAP in SCZ is not attributable to antipsychotic treatment. Our findings indicate that astrocyte pathology may be associated with psychotic symptoms. Lack of ALDH1L1 and vimentin variability and increased GFAP levels may imply that astrocyte numbers are unchanged but astrocytes are partially activated, or may indicate a specific dysregulation of GFAP.

Differential effects of GH and GH-releasing peptide-6 on astrocytes

GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 μg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 μg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3'-kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway.

Impact of omega‐6 polyunsaturated fatty acid supplementation and γ‐aminobutyric acid on astrogliogenesis through the endocannabinoid system

Neural stem cells express cannabinoid CB1 and CB2 receptors and the enzymes for the biosynthesis and metabolism of endocannabinoids (eCBs). Here we have studied the role of neural stem cell-derived eCBs as autonomous regulatory factors during differentiation. First, we examined the effect of an indirect eCB precursor linoleic acid (LA), a major dietary omega-6 fatty acid, on the eCB system in neural stem/progenitor cells (NSPCs) cultured in DMEM/F12 supplemented with N2 (N2/DF) as monolayer cells. LA upregulated eCB system-related genes and 2-arachidonoylglycerol (2-AG), but not anandamide (AEA), levels. Glial fibrillary acidic protein (GFAP) was significantly higher under LA-enriched conditions, and this effect was inhibited by the cannabinoid receptor type-1 (CB1) antagonist AM251. Second, the levels of AEA and 2-AG, as well as of the mRNA of eCB system-related genes, were measured in NSPCs after γ-aminobutyric acid (GABA) treatment. GABA upregulated AEA levels significantly in LA-enriched cultures and increased the mRNA expression of the 2-AG-degrading enzyme monoacylglycerol lipase. These effects of GABA were reproduced under culture conditions using neurobasal media supplemented with B27, which is commonly used for neurosphere culture. GABA stimulated astroglial differentiation in this medium as indicated by increased GFAP levels. This effect was abolished by AM251, suggesting the involvement of AEA and CB1 in GABA-induced astrogliogenesis. This study highlights the importance of eCB biosynthesis and CB1 signalling in the autonomous regulation of NSPCs and the influence of the eCB system on astrogliogenesis induced by nutritional factors or neurotransmitters, such as LA and GABA.

Effect of estrogen on manganese-induced toxicity on embryonic astrocytes

Manganese (Mn) is a natural trace metal that is essential for many physiological functions in the human body. Astrocytes in the central nervous system are susceptible reservoirs for Mn accumulation. Estrogen, a steroidal hormone, has been shown to mitigate Mn-induced toxicity in cultures of postnatal astrocytes. However, differences in expression/inducibility of glutamate transporters and glutamine synthetase, transmitters, and the natural gonadal steroids and their receptors are known to occur in astrocyte cultures derived from various stages of fetal and postnatal development. Cultures of embryonic (E18) hippocampal astrocytes were examined in this study for the ability of 17 β-estradiol (E2) to protect them from Mn toxicity by up regulating gene expression of a glutamate transporter. Primary rat hippocampal astrocytes were pretreated with β-Estradiol (E2) in vitro and subsequently, Mn sulfate (MnSO4). The amount of toxic damage to the astrocytes was measured by quantifying glial fibrillary acidic protein (GFAP) with a sandwiched Enzyme-Linked Immunosorbent Assay (ELISA). ELISA analysis indicated Mn exposure at 100 μM, 300 μM, or 600 μM significantly increased GFAP levels. However, E2 concentrations at 10 nM or 30 nM significantly reduced Mn-induced GFAP concentrations at 100 μM. Cells pretreated with 10 nM or 30 nM of E2 significantly lowered GFAP levels. The Water-Soluble Tetrazolium-8 (WST-8) method was utilized to determine cell viability. The WST-8 assay showed that Mn concentrations of 100 μM, 300 μM, or 600 μM significantly reduced the dehydrogenase activity, thereby decreasing the number of viable astrocytes. Enzyme activity with 600 μM of Mn was significantly decreased when compared with 100 μM of Mn, revealing a dose-dependent effect. However, the dehydrogenase activity in cells treated with 600 μM Mn was significantly increased when pretreated with 10 nM of E2. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) was used to measure changes in glutamate transporter-1 gene expression in astrocytes after pretreatment of E2 and subsequently, Mn. PCR analysis showed that when cells were exposed to 300 μM Mn, the GLT-1 gene expression was reduced compared to the control. Data also showed that the GLT-1 mRNA was upregulated in cells pretreated with 10 nM E2. When the cells were pretreated with 10 nM E2 and subsequently, 300 μM Mn, there was an increase in the GLT-1 gene expression. The experimental results indicate that E2 can attenuate some Mn-induced toxicity in E18 astrocytes.

Magnolol Protects against MPTP/MPP+-Induced Toxicity via Inhibition of Oxidative Stress inIn VivoandIn VitroModels of Parkinson’s Disease

The aim of this study is to investigate the role of magnolol in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-) induced neurodegeneration in mice and 1-methyl-4-phenylpyridinium ion-(MPP+-) induced cytotoxicity to human neuroblastoma SH-SY5Y cells and to examine the possible mechanisms. Magnolol (30 mg/kg) was orally administered to C57BL/6N mice once a day for 4 or 5 days either before or after MPTP treatment. Western blot analysis revealed that MPTP injections substantially decreased protein levels of dopamine transporter (DAT) and tyrosine hydroxylase (TH) and increased glial fibrillary acidic protein (GFAP) levels in the striatum. Both treatments with magnolol significantly attenuated MPTP-induced decrease in DAT and TH protein levels in the striatum. However, these treatments did not affect MPTP-induced increase in GFAP levels. Moreover, oral administration of magnolol almost completely prevented MPTP-induced lipid peroxidation in the striatum. In human neuroblastoma SH-SY5Y cells, magnolol significantly attenuated MPP+-induced cytotoxicity and the production of reactive oxygen species. These results suggest that magnolol has protective effects via an antioxidative mechanism in both in vivo and in vitro models of Parkinson's disease.

Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling

Glial fibrillary acidic protein (GFAP) is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole-body cooling. We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole-body cooling to gestational age-matched controls without neurological injury and neonates with HIE by brain abnormalities on magnetic resonance imaging (MRI). Neonates with HIE had increased GFAP levels compared with controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared with neonates with HIE and normal imaging. Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers such as GFAP could help triage neonates with HIE to treatment, measure treatment efficacy, and provide prognostic information.

Insulin and growth hormone-releasing peptide-6 (GHRP-6) have differential beneficial effects on cell turnover in the pituitary, hypothalamus and cerebellum of streptozotocin (STZ)-induced diabetic rats

Poorly controlled type1 diabetes is associated with hormonal imbalances and increased cell death in different tissues, including the pituitary, hypothalamus and cerebellum. In the pituitary, lactotrophs are the cell population with the greatest increase in cell death, whereas in the hypothalamus and cerebellum astrocytes are most highly affected. Insulin treatment can delay, but does not prevent, diabetic complications. As ghrelin and growth hormone (GH) secretagogues are reported to prevent apoptosis in different tissues, and to modulate glucose homeostasis, a combined hormonal treatment may be beneficial. Hence, we analyzed the effect of insulin and GH-releasing peptide 6 (GHRP-6) on diabetes-induced apoptosis in the pituitary, hypothalamus and cerebellum of diabetic rats. Adult male Wistar rats were made diabetic by streptozotocin injection (65 mg/kg ip) and divided into four groups from diabetes onset: those receiving a daily sc injection of saline (1 ml/kg/day), GHRP-6 (150 μg/kg/day), insulin (1–8 U/day) or insulin plus GHRP-6 for 8 weeks. Control non-diabetic rats received saline (1 ml/kg/day). Diabetes increased cell death in the pituitary, hypothalamus and cerebellum ( P < 0.05). In the pituitary, insulin treatment prevented diabetes-induced apoptosis ( P < 0.01), as well as the decline in prolactin and GH mRNA levels ( P < 0.05). In the hypothalamus, neither insulin nor GHRP-6 decreased diabetes-induced cell death. However, the combined treatment of insulin + GHRP-6 prevented the diabetes induced-decrease in glial fibrillary acidic protein (GFAP) levels ( P < 0.05). In the cerebellum, although insulin treatment increased GFAP levels ( P < 0.01), only the combined treatment of insulin + GHRP-6 decreased diabetes-induced apoptosis ( P < 0.05). In conclusion, insulin and GHRP-6 exert tissue specific effects in STZ-diabetic rats and act synergistically on some processes. Indeed, insulin treatment does not seem to be effective on preventing some of the diabetes-induced alterations in the central nervous system.

Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis

The major intermediate cytoskeletal protein of astrocytes, glial fibrillary acidic protein (GFAP), and that of axons, neurofilament light protein (NFL), may both be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). We investigated GFAP and NFL levels in CSF as possible biomarkers for progression in multiple sclerosis (MS). Patients with relapsing-remitting MS (RRMS, n = 15) or secondary progressive MS (SPMS, n = 10) and healthy control subjects (n = 28) were examined twice with an interval of 8-10 years apart. Neurological deficits were scored with the Expanded Disability Status Scale (EDSS). GFAP and NFL levels were determined in CSF by enzyme-linked immunosorbent assay (ELISA). GFAP levels and NFL levels correlated with age (r and r (s) = 0.50, p = 0.006). Adjusting for age, MS patients had increased GFAP levels compared with controls (p = 0.03) and GFAP levels correlated with neurological disability (EDSS, r = 0.51, p < 0.05) and disease progression [Multiple Sclerosis Severity Score (MSSS), r = 0.47, p < 0.05]. The mean annual increase of GFAP was 6.5 ng/L for controls, 8.1 ng/L for RRMS patients, and 18.9 ng/L for SPMS patients. GFAP level at the first examination had predictive value for neurological disability 8-10 years later (EDSS, r = 0.45, p < 0.05) but not for EDSS increase between the examinations. NFL levels were not significantly increased in MS patients compared with controls and had no relationship to disability or progression and no prognostic value for disability development. GFAP, a marker for astrogliosis, is a potential biomarker for MS progression and may have a role in clinical trials for assessing the impact of therapies on MS progression.

Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats

Little is known about the effects of manganese (Mn) exposure over neurodevelopment and whether these early insults result in effects lasting into adulthood. To determine if early Mn exposure produces lasting neurobehavioral and neurochemical effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND 1-21) and evaluated (1) behavioral performance in the open arena in the absence (PND 97) and presence (PND 98) of a d-amphetamine challenge, (2) brain dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal cortex, striatum, and nucleus accumbens (PND 107), and (3) astrocyte marker glial fibrillary acidic protein (GFAP) levels in these same brain regions (PND 24 and 107). We found that preweaning Mn exposure did not alter locomotor activity or behavior disinhibition in adult rats, though Mn-exposed animals did exhibit an enhanced locomotor response to d-amphetamine challenge. Preweaning Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens and prefrontal cortex, respectively, compared with controls. We also found increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings, and increased GFAP levels in prefrontal cortex, medial striatum and nucleus accumbens of adult (PND 107) rats exposed to preweaning Mn, indicating an effect of Mn exposure on astrogliosis that persisted and/or progressed to other brain regions in adult animals. These data show that preweaning Mn exposure leads to lasting molecular and functional impacts in multiple brain regions of adult animals, long after brain Mn levels returned to normal.

GFAP expression in the rat brain following sub-chronic exposure to a 900 MHz electromagnetic field signal

Purpose: The rapid development and expansion of mobile communications contributes to the general debate on the effects of electromagnetic fields emitted by mobile phones on the nervous system. This study aims at measuring the glial fibrillary acidic protein (GFAP) expression in 48 rat brains to evaluate reactive astrocytosis, three and 10 days after long-term head-only sub-chronic exposure to a 900 MHz electromagnetic field (EMF) signal, in male rats.Methods: Sprague-Dawley rats were exposed for 45 min/day at a brain-averaged specific absorption rate (SAR) = 1.5 W/kg or 15 min/day at a SAR = 6 W/kg for five days per week during an eight-week period. GFAP expression was measured by the immunocytochemistry method in the following rat brain areas: Prefrontal cortex, cerebellar cortex, dentate gyrus of the hippocampus, lateral globus pallidus of the striatum, and the caudate putamen.Results: Compared to the sham-treated rats, those exposed to the sub-chronic GSM (Global System for mobile communications) signal at 1.5 or 6 W/kg showed an increase in GFAP levels in the different brain areas, three and ten days after treatment.Conclusion: Our results show that sub-chronic exposures to a 900 MHz EMF signal for two months could adversely affect rat brain (sign of a potential gliosis).

Population Variation in Glial Fibrillary Acidic Protein Levels in Brain Ageing: Relationship to Alzheimer-Type Pathology and Dementia

Background: The cellular pathology of astrocytes in brain ageing and their role in modulating the brain’s response to neurodegenerative pathology remain incompletely understood. Methods: Using quantitative ELISA, we have investigated glial fibrillary acidic protein (GFAP) expression in the population-based neuropathology cohort of the Medical Research Council Cognitive Function and Ageing Study to determine: (1) the population variation in the astroglial hypertrophic response, (2) its relationship to the presence of Alzheimer-type pathology, and (3) its association with cognition. Results: Increasing GFAP was found with increasing Braak stage, levels increasing even at early stages. Within Braak stages, GFAP did not differ between demented and non-demented individuals, but there was greater variance in GFAP in the demented. Possession of ApoE ε4 was associated with slightly increased GFAP levels (not significant) for given amyloid β protein loads. Conclusion: In a population-based sample, increasing gliosis precedes development of Alzheimer lesions. Population variation in GFAP with varying Alzheimer lesion burdens suggests that they are not the only driver for astrogliosis. GFAP was not independently predictive of dementia, but the variation in astrocytic responses may be a factor modulating brain responses to neurodegenerative pathology.