Publications by authors named "Domenico L Di Curzio"

10 Publications

  • Page 1 of 1

Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus.

Fluids Barriers CNS 2018 May 3;15(1):14. Epub 2018 May 3.

Department of Pathology, University of Manitoba, 401-727 McDermot Avenue, Winnipeg, MB, R3E 3P5, Canada.

Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies.
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http://dx.doi.org/10.1186/s12987-018-0099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932868PMC
May 2018

Memantine treatment of juvenile rats with kaolin-induced hydrocephalus.

Brain Res 2018 06 3;1689:54-62. Epub 2018 Apr 3.

Department of Pathology, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada. Electronic address:

Memantine is a selective, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has previously been shown to have neuroprotective qualities in some animal models of neurologic disease. We hypothesized that memantine therapy would improve behavioral, neuropathological, and/or biochemical outcomes in juvenile rats with kaolin-induced hydrocephalus. Three-week old rats received an injection of kaolin (aluminum silicate) into the cisterna magna. Magnetic resonance imaging was performed one week later to assess ventricle size and stratify rats to three treatment groups. Rats were blindly treated daily for three weeks with saline or 10 or 30 mg/kg/day memantine. Behavior measures were performed weekly. Histologic and biochemical evaluations were performed at termination. Hydrocephalic rats showed no differences in weight among treatment groups. Memantine treatment stabilized ventricular enlargement in both low and high dose groups. The high dose group exhibited increased motor activity in open field chambers compared to the vehicle-treated group. However, there were no significant differences between the three hydrocephalic treatment groups for other behavioral tasks. Ventriculomegaly was associated with periventricular white matter damage. Glial fibrillary acidic protein (GFAP) content was higher in the low dose memantine group compared to vehicle-treated group, but there were no differences in GFAP-immunoreactive astrocytes or Iba-1- immunoreactive microglia between groups. Memantine therapy stabilized ventricular expansion and improved some behavioral measures but did not reduce brain tissue changes in juvenile rats with kaolin-induced hydrocephalus.
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http://dx.doi.org/10.1016/j.brainres.2018.04.001DOI Listing
June 2018

T, diffusion tensor, and quantitative magnetization transfer imaging of the hippocampus in an Alzheimer's disease mouse model.

Magn Reson Imaging 2018 07 12;50:26-37. Epub 2018 Mar 12.

Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Radiology, University of Manitoba, Winnipeg, MB R3E 0T6, Canada; Physics, University of Winnipeg, R3B 2N2, Canada.

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aβ accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD.
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http://dx.doi.org/10.1016/j.mri.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461204PMC
July 2018

Magnesium sulfate treatment for juvenile ferrets following induction of hydrocephalus with kaolin.

Fluids Barriers CNS 2016 Apr 27;13. Epub 2016 Apr 27.

Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.

Background: Previous work with 3-week hydrocephalic rats showed that white matter damage could be reduced by the calcium channel antagonist magnesium sulfate (MgSO4). We hypothesized that MgSO4 therapy would improve outcomes in ferrets with hydrocephalus induced with kaolin at 15 days.

Methods: MRI was performed at 29 days to assess ventricle size and stratify ferrets to treatment conditions. Beginning at 31 days age, they were treated daily for 14 days with MgSO4 (9 mM/kg/day) or sham saline therapy, and then imaged again before sacrifice. Behavior was examined thrice weekly. Histological and biochemical ELISA and myelin enzyme activity assays were performed at 46 days age.

Results: Hydrocephalic ferrets exhibited some differences in weight and behavior between treatment groups. Those receiving MgSO4 weighed less, were more lethargic, and displayed reduced activity compared to those receiving saline injections. Hydrocephalic ferrets developed ventriculomegaly, which was not modified by MgSO4 treatment. Histological examination showed destruction of periventricular white matter. Glial fibrillary acidic protein content, myelin basic protein content, and myelin enzyme activity did not differ significantly between treatment groups.

Conclusion: The hydrocephalus-associated disturbances in juvenile ferret brains are not ameliorated by MgSO4 treatment, and lethargy is a significant side effect.
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http://dx.doi.org/10.1186/s12987-016-0031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848861PMC
April 2016

Nonsurgical therapy for hydrocephalus: a comprehensive and critical review.

Fluids Barriers CNS 2016 Feb 5;13. Epub 2016 Feb 5.

Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada.

Pharmacological interventions have been tested experimentally and clinically to prevent hydrocephalus and avoid the need for shunting beginning in the 1950s. Clinical trials of varied quality have not demonstrated lasting and convincing protective effects through manipulation of cerebrospinal fluid production, diuresis, blood clot fibrinolysis, or manipulation of fibrosis in the subarachnoid compartment, although there remains some promise in the latter areas. Acetazolamide bolus seems to be useful for predicting shunt response in adults with hydrocephalus. Neuroprotection in the situation of established hydrocephalus has been tested experimentally beginning more recently. Therapies designed to modify blood flow or pulsation, reduce inflammation, reduce oxidative damage, or protect neurons are so far of limited success; more experimental work is needed in these areas. As has been recommended for preclinical studies in stroke and brain trauma, stringent conditions should be met for preclinical studies in hydrocephalus.
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http://dx.doi.org/10.1186/s12987-016-0025-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743412PMC
February 2016

Oral antioxidant therapy for juvenile rats with kaolin-induced hydrocephalus.

Fluids Barriers CNS 2014 13;11:23. Epub 2014 Oct 13.

Manitoba Institute of Child Health, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada ; Department of Pathology, University of Manitoba, 727 McDermot Avenue, Winnipeg, R3E 3P5, Canada.

Background: Oxidative and nitrosylative changes have been shown to occur in conjunction with the hypoxic changes and cellular/axonal damage in hydrocephalic rodent brains. We hypothesized that antioxidant therapy would improve behavioral, neurophysiological, and/or neurobiochemical outcomes in juvenile rats following induction of hydrocephalus.

Methods: Three-week old rats received an injection of kaolin (aluminum silicate) into the cisterna magna. Magnetic resonance (MR) imaging was performed two weeks later to assess ventricle size and stratify rats to four treatment conditions. Rats were treated for two weeks daily with sham therapy of either oral canola oil or dextrose or experimental therapy of a low or high dose of an antioxidant mixture containing α-tocopherol, L-ascorbic acid, coenzyme Q10 (CoQ10), reduced glutathione, and reduced lipoic acid. Behavior was examined thrice weekly.

Results: All hydrocephalic groups lagged in weight gain in comparison to non-hydrocephalic controls, all developed significant ventriculomegaly, and all exhibited white matter destruction. Canola oil with or without the antioxidant mixture normalized antioxidant capacity in brain tissue, and the dextrose-treated rats had the greatest ventricular enlargement during the treatment period. However, there were no significant differences between the four treatment groups of hydrocephalic rats for the various behavioral tasks. Glial fibrillary acidic protein and myelin basic protein quantitation showed no differences between the treatment groups or with control rats. There was increased lipid peroxidation in the hydrocephalic rats compared to controls but no differences between treatment groups.

Conclusion: The antioxidant cocktail showed no therapeutic benefits for juvenile rats with kaolin-induced hydrocephalus although canola oil might have mild benefit.
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http://dx.doi.org/10.1186/2045-8118-11-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199774PMC
October 2014

Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice.

Magn Reson Imaging 2013 Nov 29;31(9):1515-21. Epub 2013 Aug 29.

Department of Physics, University of Winnipeg, 515 Portage Avenue, Winnipeg, Manitoba, R3B 2E9, Canada. Electronic address:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aging populations. Although senile plaques and neurofibrillary tangles are well-established hallmarks of AD, changes in cerebral white matter correlate with cognitive decline and may increase the risk of the development of dementia. We used the triple transgenic (3xTg)-AD mouse model of AD, previously used to show that white matter changes precede plaque formation, to test the hypothesis that MRI detectable changes occur in the corpus callosum, external capsule and the fornix. T2-weighted and diffusion tensor magnetic resonance imaging and histological stains were employed to assess white matter in older (11-17months) 3xTg-AD mice and controls. We found no statistically significant changes in white matter between 3xTg-AD mice and controls, despite well-developed neurofibrillary tangles and beta amyloid immunoreactive plaques. Myelin staining was normal in affected mice. These data suggest that the 3xTg-AD mouse model does not develop MRI detectable white matter changes at the ages we examined.
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http://dx.doi.org/10.1016/j.mri.2013.06.013DOI Listing
November 2013

Pre- and post-shunting observations in adult sheep with kaolin-induced hydrocephalus.

Fluids Barriers CNS 2013 11;10:24. Epub 2013 Jul 11.

Medtronic Neurosurgery, Goleta, CA, USA.

Background: The objective of this study was to examine host-shunt interactions in sheep with kaolin-induced hydrocephalus.

Methods: Forty-two sheep (29-40 kg) were utilized for this study. In 20 animals, various kaolin doses were injected into the cisterna magna including 10 and 50 mg/kg as well as 2-4 ml of a 25% kaolin suspension. Based on animal health and hydrocephalus development, 3 ml of a 25% kaolin suspension was chosen. In 16 animals, kaolin was administered and 6-8 days later, the animals received a custom made ventriculo-peritoneal shunt. In 8 animals ventricular CSF pressures were measured with a water manometer before kaolin administration and 7-8 days later. The sheep were allowed to survive for up to 9-12 weeks post-kaolin or until clinical status required euthanasia. Brains were assessed for morphological and histological changes. Ventricle/cerebrum cross sectional area ratios (V/C) were calculated from photographs of the sliced coronal planes immediately anterior to the interventricular foramina.

Results: Intraventricular pressures increased from 12.4±1.1 cm H2O to 41.3±3.5 cm H2O following kaolin injection (p < 0.0001, n = 8). In all animals, we observed kaolin on the basal surface of the brain and mild (V/C 0.03-0.10) to moderate (V/C >0.10) ventricular expansion. The animals lost weight between kaolin administration and shunting (33.7±1.2 kg versus 31.0±1.7 kg) with weights after shunting remaining stable up to sacrifice (31.6±2.2 kg). Of 16 shunted animals, 5 did well and were sacrificed 9-12 weeks post-kaolin. In the remainder, the study was terminated at various times due to deteriorating health. Hydrocephalus was associated with thinning of the corpus callosum, but no obvious loss of myelin staining, along with reactive astroglial (glial fibrillary acidic immunoreactive) and microglial (Iba1 immunoreactive) changes in the white matter. Ventricular shunts revealed choroid plexus ingrowth in 5/16, brain tissue ingrowth in 1/16, problems with shunt insertion in 3/16, occlusion by hemorrhagic-inflammatory material in 5/16, or no obstruction in 2/16. Free flowing CSF indicated that the peritoneal catheter was patent.

Conclusions: Cerebrospinal fluid shunts in hydrocephalic sheep fail in ways that are reminiscent of human neurosurgical experience suggesting that this model may be helpful in the development of more effective shunt technology.
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http://dx.doi.org/10.1186/2045-8118-10-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726403PMC
May 2014

Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus.

Exp Neurol 2013 Oct 12;248:112-28. Epub 2013 Jun 12.

Department of Human Anatomy & Cell Science, University of Manitoba, Canada; Manitoba Institute of Child Health, Canada.

Hydrocephalus is a neurological condition characterized by altered cerebrospinal fluid (CSF) flow with enlargement of ventricular cavities in the brain. A reliable model of hydrocephalus in gyrencephalic mammals is necessary to test preclinical hypotheses. Our objective was to characterize the behavioral, structural, and histological changes in juvenile ferrets following induction of hydrocephalus. Fourteen-day old ferrets were given an injection of kaolin (aluminum silicate) into the cisterna magna. Two days later and repeated weekly until 56 days of age, magnetic resonance (MR) imaging was used to assess ventricle size. Behavior was examined thrice weekly. Compared to age-matched saline-injected controls, severely hydrocephalic ferrets weighed significantly less, their postures were impaired, and they were hyperactive prior to extreme debilitation. They developed significant ventriculomegaly and displayed white matter destruction. Reactive astroglia and microglia detected by glial fibrillary acidic protein (GFAP) and Iba-1 immunostaining were apparent in white matter, cortex, and hippocampus. There was a hydrocephalus-related increase in activated caspase 3 labeling of apoptotic cells (7.0 vs. 15.5%) and a reduction in Ki67 labeling of proliferating cells (23.3 vs. 5.9%) in the subventricular zone (SVZ). Reduced Olig2 immunolabeling suggests a depletion of glial precursors. GFAP content was elevated. Myelin basic protein (MBP) quantitation and myelin biochemical enzyme activity showed early maturational increases. Where white matter was not destroyed, the remaining axons developed myelin similar to the controls. In conclusion, the hydrocephalus-induced periventricular disturbances may involve developmental impairments in cell proliferation and glial precursor cell populations. The ferret should prove useful for testing hypotheses about white matter damage and protection in the immature hydrocephalic brain.
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http://dx.doi.org/10.1016/j.expneurol.2013.06.004DOI Listing
October 2013

The genetic basis of adrenal gland weight and structure in BXD recombinant inbred mice.

Mamm Genome 2011 Apr 24;22(3-4):209-34. Epub 2011 Feb 24.

John Buhler Research Centre, Department of Human Anatomy and Cell Science, University of Manitoba, Winnpeg, R3L 3P4, MB, Canada.

Adrenal gland function is mediated through secreted hormones, which play a vital role in the autonomic and hypothalamic-pituitary-adrenal (HPA)-axis-mediated stress response. The genetic underpinnings of the stress response can be approached using a quantitative trait locus (QTL) analysis. This method has been used to investigate genomic regions associated with variation in complex phenotypes, but it has not been used to explore the structure of the adrenal. We used QTL analyses to identify candidate genes underlying adrenal weight and adrenal cortical zone and medulla widths. We used 64 BXD recombinant inbred (RI) strains of mice (n = 528) and 2 parental strains (C57BL/6J and DBA/2J; n = 20) to measure adrenal weights and adrenal zone widths. For adrenal weight, we found significant QTLs on chromosome 3 for females (Fawq1) and Chr 4 for males (Mawq1) and suggestive QTLs on Chrs 1, 3, 10, and 14 for females and Chrs 2, 4, 10, 17, and X for males. We identified a significant QTL on Chr 10 (Mawdq1) and a suggestive QTL on Chr 13 for male adrenal total width. For male adrenal medulla width, we found a significant QTL on Chr 5 (Mmwdq1) and a suggestive QTL on Chr 1. We also identified significant QTLs on Chrs 10 (Mxwdq1) and 14 (Mxwdq2) for male X-zone width. There are 113 genes that mapped within the significant QTL intervals, and we identified 4 candidate genes associated with adrenal structure and/or function. In summary, this study is an important first step for detecting genetic factors influencing the structure of the adrenal component of the HPA axis using QTL analyses, which may relate to adrenal function and provide further insights into elucidating genes critical for stress-related phenotypes.
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http://dx.doi.org/10.1007/s00335-011-9315-9DOI Listing
April 2011