Minocycline treatment following hypoxic/ischaemic injury attenuates white matter injury in a rodent model of periventricular leucomalacia.

AIMS: Periventricular white matter injury in premature infants occurs following hypoxia/ischaemia and systemic infection, and results in hypomyelination, as well as neuromotor and cognitive deficits later in life. Inflammatory infiltrates are seen within human cerebral white matter from periventricular leucomalacia (PVL) cases. METHODS: In this study, we examine the time course of CD-68+ microglial cell responses relative to cell death within white matter following hypoxia/ischaemia in a rat model of PVL. We also tested the efficacy of the minocycline, an agent that suppresses microglial activation, in this model when administered as a post-insult treatment. RESULTS: We show that preoligodendrocyte injury in the post-natal day 6 begins within 24 h and continues for 48-96 h after hypoxia/ischaemia, and that microglial responses occur primarily over the first 96 h following hypoxia/ischaemia. Minocycline treatment over this 96 h time window following the insult resulted in significant protection against white matter injury, and this effect was concomitant with a reduction in CD-68+ microglial cell numbers. CONCLUSIONS: These results suggest that anti-inflammatory treatments may represent a useful strategy in the treatment of PVL, where clinical conditions would favour a post-insult treatment strategy.

Relationship between body composition and skeletal muscle eNOS.

OBJECTIVE: Owing to the relationship between nitric oxide related endothelial dysfunction, insulin resistance and cardiovascular disease in overweight individuals, we investigated if skeletal muscle endothelial nitric oxide synthase (eNOS) protein content and activity are lower in overweight than lean women. DESIGN: A total of 19 women (age 26.0+/-1.7 years) underwent a resting muscle biopsy, body composition analysis by hydrostatic weighing and peak aerobic capacity determination using indirect calorimetry (Study 1). An additional separate set of six lean (< or = 25% fat) and six overweight (>25% fat) women were subsequently studied for the determination of eNOS activity, and to better control for absolute peak aerobic capacity between lean and overweight women (Study 2). RESULTS: Skeletal muscle eNOS content was inversely related to percent body fat (r2 = 0.58, P < 0.01), and body mass index (r2 = 0.35, P < 0.05). Total eNOS activity was lower in overweight than lean women (2.09 +/- 0.22 vs 1.44 +/- 0.17 U, P < 0.05; n = 12), and was inversely related to percent body fat (r2 = 0.32, P = 0.05), and BMI (r 2 = 0.41, P < 0.05). Absolute and relative aerobic capacity were not independent predictors of skeletal muscle eNOS content (r2 = 0.11 and 0.26, respectively). CONCLUSION: There is an inverse relationship between eNOS and percent body fat that may have implications for the previously reported reduced endothelial function and insulin sensitivity in overweight women.

Pathophysiology, prevention, and potential treatment of neural tube defects.

Neural tube defects (NTD) remain a major cause of morbidity in spite of the reduction in liveborn incidence with periconceptional folic acid. However, the etiology remains unknown. This article reviews studies that address causation and potential treatment of NTD in humans and in animal models that resemble aspects of the common human NTD. Studies of nutritional markers of vitamin B12 and folic acid support a defect in homocysteine metabolism; a thermolabile variant of methylene tetrahydrofolate reductase, an enzyme that remethylates homocysteine to methionine, correlates with a risk of NTD in some human populations. Numerous mouse mutant models of NTD exist, attesting to the ease of disruption of neurulation, and a genetic basis for this malformation. Of these models, the curly tail mouse mutant most closely resembles the common human NTD. Folic acid does not prevent NTD in this model; however inositol supplementation does result in a significant reduction in incidence. Recent advances in fetal surgery, and evidence from mechanically created myelomeningocele in large animals amenable to surgical intervention suggest that the handicaps associated with myelomeningocele and associated Chiari Type II malformation may be prevented by in utero NTD closure. Success will depend on preservation of neurological tissue until such intervention is possible. Further research in animal models at the genetic and cellular levels, together with technological surgical advances, provide hope that prevention of more NTD and the associated handicaps may be possible. MRDD Research Reviews 6:6-14, 2000.