Blood-brain barrier dysfunction significantly correlates with serum matrix metalloproteinase-7 (MMP-7) following traumatic brain injury.

OBJECTIVES: To determine if radiological evidence of blood brain barrier (BBB) dysfunction, measured using Dynamic Contrast Enhanced MRI (DCE-MRI), correlates with serum matrix metalloproteinase (MMP) levels in traumatic brain injury (TBI) patients, and thereby, identify a potential biomarker for BBB dysfunction. PATIENTS AND METHODS: 20 patients with a mild, moderate, or severe TBI underwent a DCE-MRI scan and BBB dysfunction was interpreted from KTrans. KTrans is a measure of capillary permeability that reflects the efflux of gadolinium contrast into the extra-cellar space. The serum samples were concurrently collected and later analysed for MMP-1, -2, -7, -9, and -10 levels using an ELISA assay. Statistical correlations between MMP levels and the KTrans value were calculated. Multiple testing was corrected using the Benjamin-Hochberg method to control the false-discovery rate (FDR). RESULTS: Serum MMP-1 values ranged from 1.5 to 49.6 ng/ml (12 ± 12.7), MMP-2 values from 58.3 to 174.1 ng/ml (109.5 ± 26.7), MMP-7 from 1.5 to 31.5 ng/mL (10 ± 7.4), MMP-9 from 128.6 to 1917.5 ng/ml (647.7 ± 749.6) and MMP-10 from 0.1 to 0.6 ng/mL (0.3 ± 0.2). Non-parametric Spearman correlation analysis on the data showed significant positive relationship between KTrans and MMP-7 (r = 0.55, p < 0.01). Correlations were also found between KTrans and MMP-1 (r = 0.74, p < 0.0002) and MMP-2 (r = 0.5, p < 0.025) but the actual MMP values were not above reference ranges, limiting the interpretation of results. Statistically significant correlations between KTrans and either MMP-9 or -10 were not found. CONCLUSION: This is the first study to show a correlation between DCE measures and MMP values in patients with a TBI. Our results support the suggestion that serum MMP-7 may be considered as a peripheral biomarker quantifying BBB dysfunction in TBI patients.

Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury.

Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs-miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128-were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival.

Mid-Gestational Enlargement of Fetal Thalami in Women Exposed to Methadone during Pregnancy.

Methadone maintenance therapy is the standard of care in many countries for opioid-dependent women who become pregnant. Despite recent evidence showing significant neurodevelopmental changes in children and adults exposed to both licit and illicit substances in utero, data on the effects of opioids in particular remains scarce. The purpose of this study was to examine the effects of opiate use, in particular methadone, on various fetal cortical and biometric growth parameters in utero using ultrasound measurements done at 18-22 weeks gestation. Head circumference (HC), bi-parietal diameter, lateral ventricle diameter, transcerebellar diameter, thalamic diameter, cisterna magna diameter, and femur length were compared between fetuses born to methadone-maintained mothers and non-substance using controls. A significantly larger thalamic diameter (0.05 cm, p = 0.01) was observed in the opiate-exposed group. Thalamic diameter/HC ratio was also significantly raised (0.03 mm, p = 0.01). We hypothesize here that the increase in thalamic diameter in opiate-exposed fetuses could potentially be explained by regional differences in opioid and serotonin receptor densities, an alteration in monoamine neurotransmitter systems, and an enhancement of the normal growth increase that occurs in the thalamus during mid-gestation.

Pharmacological treatment of neonatal opiate withdrawal: between the devil and the deep blue sea.

Illicit drug use with opiates in pregnancy is a major global health issue with neonatal withdrawal being a common complication. Morphine is the main pharmacological agent administered for the treatment of neonatal withdrawal. In the past, morphine has been considered by and large inert in terms of its long-term effects on the central nervous system. However, recent animal and clinical studies have demonstrated that opiates exhibit significant effects on the growing brain. This includes direct dose-dependent effects on reduction in brain size and weight, protein, DNA, RNA, and neurotransmitters-possibly as a direct consequence of a number of opiate-mediated systems that influence neural cell differentiation, proliferation, and apoptosis. At this stage, we are stuck between the devil and the deep blue sea. There are no real alternatives to pharmacological treatment with opiates and other drugs for neonatal opiate withdrawal and opiate addiction in pregnant women. However, pending further rigorous studies examining the potential harmful effects of opiate exposure in utero and the perinatal period, prolonged use of these agents in the neonatal period should be used judiciously, with caution, and avoided where possible.