Hypoxia inducible factor and diffuse white matter injury in the premature brain: perspectives from genetic studies in mice

Glutamate toxicity from hypoxia-ischaemia during the perinatal period causes white matter injury that can result in long-term motor and intellectual disability. Blocking ionotropic glutamate receptors (GluRs) has been shown to inhibit oligodendrocyte injury in vitro, but GluR antagonists have not yet proven helpful in clinical studies. The opposite approach of activating GluRs on developing oligodendrocytes shows promise in experimental studies on rodents as reported by Jartzie et al., in this issue. Group I metabotropic glutamate receptors (mGluRs) are expressed transiently on developing oligodendrocytes in humans during the perinatal period, and the blood–brain-barrier permeable agonist of group I mGluRs, 1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), reduces white matter damage significantly in a rat model of perinatal hypoxia-ischaemia. The results suggest drugs activating this class of GluRs could provide a new therapeutic approach for preventing cerebral palsy and other neurological consequences of diffuse white matter injury in premature infants.

Download Full-text

Abstract WMP118: Involvement of MMP-9 in Inflammation-induced White Matter Injury in a Novel Rat Model of Vascular Cognitive Impairment

Stroke ◽

10.1161/str.44.suppl_1.awmp118 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Fakhreya Y Jalal ◽

Jeffrey Thompson ◽

Yi Yang ◽

Gary A Rosenberg

Keyword(s):

T Cells ◽

Cognitive Impairment ◽

White Matter ◽

Rat Model ◽

Hypoxia Inducible Factor ◽

Treated Group ◽

White Matter Injury ◽

Image Size ◽

Apparent Diffusion Coefficients ◽

Long Term Treatment

Objective: We have recently developed a rat model of white matter (WM) injury in stroke-prone spontaneously hypertensive rats (SHR-SP), which shows chronic oligodendrocyte death, blood-brain barrier (BBB) disruption, and cognitive impairment. In this study, we investigated the mechanisms of white matter damage secondary to chronic hypertensive disease. Methods: At 12 weeks of age, we subjected SHR-SP to permanent unilateral carotid artery occlusion (UCAO) followed by the Japanese permissive diet (JPD) and 1 % NaCl in drinking water. One group of UCAO/JPD rats received minocycline (50 mg/kg in DMSO, i.p. every other day for 9 weeks) and another had only UCAO/JPD with DMSO. WM lesions were characterized histologically, biochemically, and by MRI; cognitive impairment was tested by Morris water maze. Results: One to 3 weeks after UCAO/JPD, we found an increase in hypoxia inducible factor-1α (HIF-1α) in astrocytes, a fall in pyrol hydroxylase-2 (PHD-2), and an increase in matrix metalloproteinase-9 (MMP-9) expression. At week 1, there was infiltration of T-cells and MMP-9 co-localized with endothelial cells and neutrophils. By 3 weeks, we observed IgG leakage, indicating disruption of the BBB, with scattered hemorrhages. Long term treatment with minocycline prevented cognitive impairment along with reduction in T2-weighted image size, apparent diffusion coefficients, and fractional anisotropy compared to the vehicle-treated group. Relative cerebral blood flow was unaffected by minocycline treatment. Conclusion: Our results suggest that hypoxic hypoperfusion of the deep WM, which occurs secondary to hypertensive damage to blood vessels, initiates expression of MMP-9 and migration of T-cells, disrupting the BBB and damaging WM. The anti-inflammatory agent, minocycline, significantly protected the deep WM from injury.

Download Full-text

Quantitative Mri Evidence for Diffuse White Matter Injury and Reduced Deep Gray Matter Volumes in Extremely Preterm Infants with Major Neonatal Morbidities

Paediatrics & Child Health ◽

10.1093/pch/14.suppl_a.32a ◽

2009 ◽

Vol 14 (suppl_A) ◽

pp. 32A-32A

Author(s):

DSC Lee ◽

J Conklin ◽

Y Bureau ◽

J Winter ◽

J Rogers ◽

...

Keyword(s):

White Matter ◽

Preterm Infants ◽

Gray Matter ◽

Quantitative Mri ◽

White Matter Injury ◽

Diffuse White Matter ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Deep Gray Matter ◽

Gray Matter Volumes

Download Full-text

Magnetic resonance imaging evaluation of radiation: Cranial radiation therapy-induced diffuse white matter injury

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e13033 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e13033-e13033

Author(s):

T. Z. Mohran ◽

M. M. Omar ◽

M. A. Hameed ◽

M. S. Elnaggar

Keyword(s):

Radiation Therapy ◽

White Matter ◽

Brain Tumors ◽

Spin Echo ◽

White Matter Injury ◽

High Signal ◽

Imaging Evaluation ◽

Post Contrast ◽

Diffuse White Matter ◽

Cranial Radiation

e13033 Background: To study the value of MRI in detection and grading of diffuse white matter injury induced by cranial radiation therapy for brain tumors and to evaluate the influence of various risk factors for its development. Methods: This study included 60 patients who had primary brain tumors and received external beam conventionally fractionated radiotherapy. Twenty-three out of 60 patients received chemotherapy after radiotherapy. Post radiotherapy follow-up MRI examination was performed for all patients at 6 weeks, 3, 6, 9, 12 months, and at more than 1 year from completion of radiotherapy. MR imaging was performed with T2-weighted turbo spin echo, fast fluid-attenuated inversion- recovery (FLAIR), T1-weighted spin-echo, and T1-weighted post-contrast spin-echo sequences. Results: Twenty-one of 60 patients (35%) developed diffuse white matter injury at a mean of 15.3 + 7.6 months from the completion of radiotherapy (range, 5–36 months). Radiation-related diffuse white matter changes were characterized as diffuse high signal intensity in the periventricular deep white matter on T2WI and FLAIR sequences. The MRI grading system of these periventricular hyperintensity (PVH) were as follow: 39 patients (65%) had no WMI (grade 0), four had grade 1 changes, three patients had grade 2 changes, nine patients had grade 3, and five patients had grade 4. They were symmetrical in 13 of 21 patients (61.9%), and asymmetrical in eight out of 21 patients (38.1%). The prevalence of diffuse matter injury found to be significantly related to the volume of irradiation (p = 0.02), fraction size (p = 0.008), and concomitant use of chemotherapy (p > 0.02)Conclusions: Diffuse white matter injury is a known consequence of radiation therapy, and the capability of detecting and grading such damage is optimally provided by MRI. No significant financial relationships to disclose.

Download Full-text