Papers by Agnieszka Cudna
Neurologia i Neurochirurgia Polska
Introduction. Our study assessed changes in concentrations of serum markers for brain damage and ... more Introduction. Our study assessed changes in concentrations of serum markers for brain damage and blood-brain barrier (BBB) dysfunction in untreated and treated Wilson's disease (WD) patients, and examined correlations between these changes and neurological impairment. Objective. These results hold the potential to determine BBB impairment and neurological advancement in WD to develop the most effective treatment for patients with severe neurological deterioration. Material and methods. The study groups included 171 patients with WD (77 with hepatic and 94 with neurological manifestations), treated either for up to 5 or 15 years, and 88 healthy controls. Serum concentrations of intercellular adhesion molecule 1 (ICAM1), P-selectin, matrix metallopeptidase 9 (MMP9), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein B (S100B) were measured before and during anti-copper treatment. The Unified Wilson's disease Rating Scale (UWDRS) was used to assess neurological advancement. Results. ICAM1 concentrations were elevated before and during anti-copper treatment compared to controls (p < 0.01), but therapy led to substantial decreases both in patients with hepatic (p < 0.01) and in patients with neurological manifestations (p < <0.05). P-selectin concentrations remained elevated before and during treatment (p < 0.05) regardless of the treatment duration and disease form. MMP9 concentrations before treatment were lower (p < 0.05), but reached control levels during treatment. GFAP concentrations were significantly elevated only in untreated patients with neurological symptoms in the longer-treated group compared to controls (p < 0.05). A significant reduction during treatment was observed only in the shorter-treated neurological group (p < 0.05). No substantial changes were observed in S100B. Only ICAM1 concentrations positively correlated (r = 0.27, p < 0.001) with the UWDRS. Conclusions. Our results provide evidence of endothelial activation in WD. However, inconclusive GFAP results, and no increase in S100B, do not allow us to conclude whether the reactive gliosis is not prominent or alternatively whether the BBB is disrupted. Elevated ICAM1 concentrations and their correlation with neurological advancement indicate BBB impairment. A decrease in ICAM1 during treatment suggests that the inflammatory process is reduced, and the BBB partially repaired. Decreased MMP9 concentrations may be the result of active liver fibrosis and higher copper concentrations. Elevated P-selectin concentrations indicate a systemic inflammatory process.
Cells, Jan 19, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences, Nov 25, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
<p>Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MP... more <p>Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40 or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. The values are expressed as mean ± SEM, for five mice per group (* represents a significant difference relative to control group, **p<0.01; <sup>#</sup> represents a significant difference compared with the MPTP group, <sup>#</sup>p<0.05; Mann Whitney <i>U</i> test).</p
<p>The mRNA expression of (A) TNF-α, (B) IL-1β, (C) IL-6, and (D) GDNF in the striatum was ... more <p>The mRNA expression of (A) TNF-α, (B) IL-1β, (C) IL-6, and (D) GDNF in the striatum was examined by real time RT-PCR. Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40, or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. Data is given as the mean value ± SEM of five animals per group (* represents a significant difference relative to the control group, *p<0.05, **p<0.01; <sup>#</sup> represents a significant difference compared with the MPTP group, <sup>#</sup>p<0.05, <sup>##</sup>p<0.01; <sup>¤</sup> differs from vehicle-treated animals, <sup>¤</sup>p<0.05, <sup>¤¤</sup>p<0.01. Mann Whitney <i>U</i> test).</p
<p>(A) DA concentration in the striata of C57Bl/10Tar mice, measured by HPLC. (B) The ratio... more <p>(A) DA concentration in the striata of C57Bl/10Tar mice, measured by HPLC. (B) The ratio of DOPAC to DA and (C) the ratio of final DA metabolite (HVA) to DA indicate the DA turnover rate. (D) Expression of tyrosine hydroxylase (TH) (the rate-limiting enzyme in catecholamine synthesis) in mice striatum was evaluated by Western blot analysis, and (E) one representative blot is shown of five independent experiments. Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40, or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. The data are shown as means ± SEM (n = 5–6) (* represents a significant difference relative to the control group, *p<0.05, **p<0.01; Mann Whitney <i>U</i> test).</p
We performed ultrastructural studies of mitochondria and evaluated the appearance of small blood ... more We performed ultrastructural studies of mitochondria and evaluated the appearance of small blood vessels of three middle-aged siblings affected by the same mutation in the NOTCH3 gene, causing CADASIL. CADASIL pathognomonic features include granular osmiophilic material (GOM), which we observed. GOMs were located in damaged and thickened basement membranes (BM) of capillaries and arterioles. Our patients were also burdened by type II diabetes (first patient), impaired glucose metabolism (second patient), and hypertension (third patient). The ultrastructure of the capillaries in the first and second patients differed from the third patient. In diabetes/impaired glucose metabolism patients (first and second patients), we observed: pathologies of mitochondria in damaged endothelium and pericytes of capillaries; extremely thickened (BM) with visible remains of vascular cells; well-preserved GOMs anchored in the rebuilt capillary extracellular matrix. We identified degenerated or vestigial small blood vessels of skeletal muscles in the first patient. The capillary damage in the third patient (with hypertension) was milder compared to the diabetes/impaired glucose metabolism patients. We conclude that in patients with a mutation in the NOTCH3 gene, the co-occurrence of diseases such as type II diabetes/impaired glucose metabolism can cause a multiplication the damages to small blood vessels by modifying/ masking the pathogenesis of CADASIL.
Medical Science Monitor, Jan 7, 2016
The aim of this study was to investigate the association between serum concentrations of the brai... more The aim of this study was to investigate the association between serum concentrations of the brain-derived neurotrophic factor (BDNF), platelet reactivity and inflammatory markers, as well as its association with BDNF encoding gene variants in type 2 diabetic patients (T2DM) during acetylsalicylic acid (ASA) therapy. This retrospective, open-label study enrolled 91 patients. Serum BDNF, genotype variants, hematological, biochemical, and inflammatory markers were measured. Blood samples were taken in the morning 2-3 h after the last ASA dose. The BDNF genotypes for selected variants were analyzed by use of the iPLEX Sequenom assay. In multivariate linear regression analysis, CADP-CT >74 sec (p<0.001) and sP-selectin concentration (p=0.03) were predictive of high serum BDNF. In multivariate logistic regression analysis, CADP-CT >74 sec (p=0.02) and IL-6 concentration (p=0.03) were risk factors for serum BDNF above the median. Non-significant differences were observed between ...
Acta neurobiologiae experimentalis, 2014
It is well established that the majority of headache and other trigeminal nerve-associated disord... more It is well established that the majority of headache and other trigeminal nerve-associated disorders have higher prevalence in females than in males. However, the pathogenesis of many chronic trigeminal pain conditions, such as trigeminal neuralgia, migraine and temporo-mandibular disorders, is still not known. One of the proposed mechanisms involve calcitonin gene-related peptide (CGRP), which is considered the most important neuropeptide in the trigeminal system. In various animal models of trigeminal nerve-associated disorders concentration of CGRP has been shown to be increased in trigeminal ganglia (TG). Moreover, intraganglionic release of CGRP has been shown to modulate neuronal transmission of pain signals. In most of these models, pathological changes in the trigeminal system are accompanied by inflammation within peripheral endings of TG neurons. The aim of the present study was to investigate the relation between gender and neurochemical changes in trigeminal ganglia evok...
OBJECTIVE Epilepsy is a chronic neurological disorder characterized by the periodic and unpredict... more OBJECTIVE Epilepsy is a chronic neurological disorder characterized by the periodic and unpredictable occurrence of seizures. The serum level of brain-derived neurotrophic factor (BDNF) has been suggested to be a potential biomarker that could detect differences in epilepsy patients. Although there is considerable neurobiological evidence linking BDNF to epilepsy, only a small number of studies investigated the relationship between BDNF serum levels and epilepsy, and these studies obtained inconsistent results. The aim of this study was to elucidate BDNF serum levels in epilepsy cases. METHODS Collectively, group of 143 patients (n = 143) were included in this study and subsequently divided into two groups consisting of individuals after singular generalized tonic-clonic seizures (n = 50) and patients with chronic epilepsy (n = 93). The samples from patients with acute epilepsy were collected 1-3 hours and 72 h after seizure, and a single collection was performed from patients with ...
Journal of Stroke and Cerebrovascular Diseases
INTRODUCTION AND OBJECTIVES Motor evoked potentials (MEPs) have been postulated to be useful in p... more INTRODUCTION AND OBJECTIVES Motor evoked potentials (MEPs) have been postulated to be useful in predicting recovery in patients with motor impairment. We aimed to investigate whether MEPs elicited by transcranial magnetic stimulation (TMS), serum brain derived neurotrophic factor (BDNF) and its genotype have prognostic value on stroke recovery in patients with hand paresis due to stroke. METHODS This was an observational cohort study. Patients underwent TMS with MEPs from abductor digiti minimi evaluation between 2-14 (D0) and 30 days (D30) after stroke and their impact on motor function of the upper limb and general outcome was assessed after 3 months (D90). The presence of a BDNF gene polymorphism was determined and serum BDNF concentrations were measured at D0, D30 and D90. RESULTS The presence of MEPs and their amplitude at rest and in effort significantly correlated with improvement of upper-limb paresis and general outcome after 3 months. Resting motor threshold did not have prognostic value. Central motor conduction time and MEP latency less consistently predicted stroke outcome or motor deficit improvement. Neither BDNF polymorphisms nor BDNF concentration at D0, D30 and D90 corresponded with the degree of paresis or the independence of patients 3 months after stroke. CONCLUSIONS The presence of MEPs and their amplitude are useful predictors of upper-limb motor function recovery and general outcome after stroke. BDNF concentration and its genotype had no prognostic value. Further studies conducted on large cohorts are necessary to determine the usefulness of these methods in motor recovery and stroke outcome prediction.
PLOS ONE
Background/Aims Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's d... more Background/Aims Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Methods IBD [0, 20, 30, 40, or 50 mg/kg] was injected b.i.d. subcutaneously for nine days to threemonth-old male C57Bl/10Tar mice, beginning two days prior to MPTP (60 mg/kg) intoxication. High-pressure liquid chromatography, Western blot analysis, and real time RT-PCR methods were applied. Results Our study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum. Moreover, IBD reduced TNF-α, IL-6, and IL-1β expression.
Pharmacological Reports
Inflammation in the orofacial region results in pain and is associated with many pathological sta... more Inflammation in the orofacial region results in pain and is associated with many pathological states, including migraine, neuralgias and temporomandibular disorder. Although extensively studied, the mechanisms responsible for these conditions are not known and effective treatments are lacking. We reported earlier that the proinflammatory cytokine tumor necrosis factor (TNF) plays an important role in regulation of trigeminal ganglion (TG) neuron function in vitro. In the present study we investigated the role of TNF in mechanical hypersensitivity in mice. We employed the Complete Freund&#39;s Adjuvant (CFA)-induced model of orofacial pain and evaluated the effect of blocking of soluble TNF activity by peripheral administration of the novel dominant negative TNF biologic, XPro1595. We show that CFA administration into the lower lip causes hyperalgesia and an increase in both expression of transient receptor potential vanilloid subfamily member 1 (TRPV1) mRNA and in the average intensity of TRPV1 protein immunoreactivity in TG neurons. We also show that intraperitoneal administration of XPro1595 prevents both CFA-induced mechanical hypersensitivity and, as shown in immunohistochemical staining - upregulation of TRPV1 protein expression in TG neurons. We conclude that one of the possible regulatory mechanisms of TNF in pain involves upregulation of the nociceptor TRPV1, and that peripheral treatment with a selective anti-soluble TNF biologic can prevent hyperalgesia caused by inflammation in the orofacial region. Therefore, these new findings suggest that XPro1595 may serve as a novel treatment for orofacial pain disorders.
Epilepsy Research, 2016
Metalloproteinase 9 (MMP9) is a member of a family of enzymes that mediate the degradation of ext... more Metalloproteinase 9 (MMP9) is a member of a family of enzymes that mediate the degradation of extracellular matrix proteins, and is especially involved in blood-brain barrier maintenance. Increased levels of MMP9 have been observed in many neurological disorders, including epilepsy, suggesting it may be involved in the pathogenesis of seizures. We investigated changes in MMP9 serum levels after acute seizures in epilepsy patients. Concentrations of MMP9 in serum were measured by ELISA in 43 patients 1-3, 24, and 72h after generalized tonic-clonic seizure and once in participants of the control group. MMP9 levels were significantly increased 1-3 and 24h after seizure and decreased to control levels 72h after seizure. Our results suggest that MMP9 is released after or just before seizure; however, further studies are needed to resolve the consequences of the observed MMP9 increase.
Neurologia i Neurochirurgia Polska, 2016
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADAS... more Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small blood vessels disease caused by mutations in the gene encoding the neurogenic locus notch homolog protein 3 (NOTCH 3). We present a Polish family with a previously unreported novel mutation in exon 12 c.1851C>C/G of the NOTCH3 gene and varying disease expression. One of the two family members with the confirmed mutation presented with all the main CADASIL symptoms; while, his affected father was nearly asymptomatic. Both family members had epilepsy, coronary artery disease, and abdominal aorta aneurysm. Our observation confirms there is phenotypic variability in CADASIL not only between, but also within, families carrying the same mutation.
Medical science monitor : international medical journal of experimental and clinical research, Jan 7, 2016
BACKGROUND The aim of this study was to investigate the association between serum concentrations ... more BACKGROUND The aim of this study was to investigate the association between serum concentrations of the brain-derived neurotrophic factor (BDNF), platelet reactivity and inflammatory markers, as well as its association with BDNF encoding gene variants in type 2 diabetic patients (T2DM) during acetylsalicylic acid (ASA) therapy. MATERIAL AND METHODS This retrospective, open-label study enrolled 91 patients. Serum BDNF, genotype variants, hematological, biochemical, and inflammatory markers were measured. Blood samples were taken in the morning 2-3 h after the last ASA dose. The BDNF genotypes for selected variants were analyzed by use of the iPLEX Sequenom assay. RESULTS In multivariate linear regression analysis, CADP-CT >74 sec (p<0.001) and sP-selectin concentration (p=0.03) were predictive of high serum BDNF. In multivariate logistic regression analysis, CADP-CT >74 sec (p=0.02) and IL-6 concentration (p=0.03) were risk factors for serum BDNF above the median. Non-signif...
Pharmacological Reports, 2015
Objective: To estimate a possible preventive effect of Ibudilast (IBD), a non-selective (3, 4, 10... more Objective: To estimate a possible preventive effect of Ibudilast (IBD), a non-selective (3, 4, 10, 11) phosphodiesterase inhibitor in the MPTP model of Parkinson’s disease. Methods: 3 months-old male C57Bl/10Tar mice were treated IBD b.i.d. for 9 days with subcutaneous injections [0, 20, 30, 40 or 50 mg/kg], beginning 2 days prior to MPTP (60 mg/kg) intoxication. Locomotor activity was examined by the RotaRod performance test. Expression of mRNA cytokines (TNFα, IL-6, IL-1β) and neurotrophic factor (GDNF) in the striatum were examined by the Real Time RT-PCR method. Micro- and astroglia activation markers (Iba-1 and GFAP, respectively) were estimated by Western blot analysis. Tyrosine hydroxylase (TH) expression and dopamine (DA) metabolism were evaluated by Western blot analysis and high-performance liquid chromatography, respectively. Results: Compared to control, IBD in the dose of 40 mg/kg significantly improved motor abilities in MPTP mice. In addition, IBD attenuated astroglia...
Objectives: The objective of our study was to evaluate various features of olfactory functioning ... more Objectives: The objective of our study was to evaluate various features of olfactory functioning in old (1 or 1.5 year) mice in two time points after MPTP intoxication (1 week and 24 weeks). Methods: The olfactory capability in mice after acute injection of MPTP was evaluated using a set of behavioral tests: 1) The Buried Food Test (BFT) to evaluate of anosmia, 2) Olfactory Discrimination Test (ODT) and 3) Olfactory Sensitivity Test (OST) to evaluate level of dysfunction of odor recognition (hyposmia). To evaluate potential disturbing effects of MPTP on motor and exploratory functioning animals were subjected to RotaRod and Open Field Test. Results: BFT results showed that time period after MPTP intoxication had influence on latency to locate the buried food, which was longer for mice 24 weeks post injury (wpi) than 7 wpi. ODT results showed a significant differences in time of exploration of new scent between controls groups and 7 wpi and 24 wpi mice respectively. Total distance pa...
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Papers by Agnieszka Cudna