Adenosine, oxidative stress and cytoprotection.

Adenosine, a metabolite of ATP, serves a number of important physiological roles in the body. These actions contribute to sedation, bradycardia, vasorelaxation, inhibition of lipolysis and regulation of the immune system and are mediated, in part, through activation of three distinct adenosine receptor (AR) subtypes. To date, four receptor types have been cloned: A1, A2A, A2B and A3. It is becoming increasing clear that adenosine contributes significantly to cytoprotection, a function mediated principally by the A1AR and A3AR. In this review, we survey the literature on the role of adenosine and the mechanisms underlying cytoprotection and ischemic preconditioning, a process characterized by cytoprotection derived from repeated brief ischemic challenges. An important recent observation is that the expression of several AR subtypes could be regulated by oxidative stress to provide a greater cytoprotective role. Thus, like other proteins known to be regulated during ischemia, the A1AR and A3AR can be considered as being inducible receptors.

Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis.

The trisomy of human chromosome 21 (Down syndrome) is the leading genetic cause of learning difficulties in children, and predisposes this population to the early onset of the neurodegeneration of Alzheimer's disease. Down syndrome is associated with increased interferon (IFN) sensitivity resulting in unexpectedly high levels of IFN inducible gene products including Fas, complement factor C3, and neuronal HLA I which could result in a damaging inflammatory reaction in the brain. Consistent with this possibility, we report here that the trisomy 16 mouse fetus has significantly increased whole brain IFN-gamma and Fas receptor immunoreactivity and that cultured whole brain trisomy 16 mouse neurons have increased basal levels of caspase 1 activity and altered homeostasis of intracellular calcium and pH. The trisomic neurons also showed a heightened sensitivity to the increase in both Fas receptor levels and caspase 1 activity we observed when IFN-gamma was added to the neuron culture media. Because of the autoregulatory nature of IFN activity, and the IFN inducing capability of caspase-1-activated cytokine activity, our data argue in favor of the possibility of an interferon-mediated, self-perpetuating, inflammatory response in the trisomy brain that could subserve the loss of neuron viability seen in this trisomy 16 mouse model for Down syndrome.

Partial IFN-alpha/beta and IFN-gamma receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viability.

The trisomy 16 mouse fetus is a well-studied model for Down syndrome (trisomy 21), the leading genetic cause of mental retardation in the newborn population. Human chromosome 21 and mouse chromosome 16 each carry a large cluster of genes that code for components of the interferon (IFN)-alpha/beta and IFN-gamma receptors, and Down syndrome cells display significantly increased sensitivity to IFN action. We have previously reported that in utero anti-IFN IgG treatment of mice pregnant with trisomy 16 fetuses results in a significant improvement in trisomy 16 fetus growth and morphology and that anti-IFN-gamma IgG treatment can prevent the premature death of trisomy 16 fetal mouse cortical neurons in culture. We have now used IFN receptor subunit knockout mice to produce mouse fetuses that carry three No. 16 chromosomes and one copy each of disabled IFN-gamma receptor (IFNGR) and IFN-alpha/beta receptor (IFNAR-2) component genes. We report here that this partial IFN receptor knockout trisomy (PIRKOT) mouse fetus has significantly improved growth and yields cortical neurons whose viability is the equivalent of that seen in their euploid counterparts.

Anti-gamma interferon can prevent the premature death of trisomy 16 mouse cortical neurons in culture.

Previous reports have indicated that human trisomy 21 and mouse trisomy 16 neurons exhibit decreased viability in culture when compared to euploid control cultures and that trisomic cells are significantly more sensitive to the anti-cellular effects of the interferons. In the study reported here, cortical neurons from euploid and trisomy 16 mouse fetuses were treated with either anti-gamma-interferon or non-specific IgG and neuron morphology and viability measured photographically. The addition of anti-gamma-interferon IgG to the culture media had no effect on euploid neurons, but significantly increased trisomy neuron viability throughout the 5-day culture period. Assay of both DNA fragmentation and phosphatidylserine externalization suggested that the trisomic neurons were undergoing apoptosis at a significantly higher rate than their euploid counterparts and that this increase in apoptosis could be almost completely prevented by addition of either ligand purified monoclonal or ligand purified polyclonal anti-gamma-interferon IgG. Taken together, these data suggest that endogenous interferon plays an important role in the premature death of the trisomy neuron.

Headache after lumbar iohexol myelography: the influence of a history of headaches and early ambulation.

Whether a history of headache or "early" versus "late" ambulation (no bed rest or bed rest for 24 h) influence the occurrence of headache after lumbar iohexol myelography was studied by blinded interviews in 158 consecutive patients referred for elective lumbar myelography (LM) because of suspected lumbar disc prolapse or spinal stenosis. Headache after LM occurred more often in patients with a history of headache (57%) than in patients without such a history (29%), P < 0.001. Patients with normal myelographic findings complained of headache after LM more often (55%) than patients with abnormal myelograms (31%), P < 0.008. No difference in the incidence of headache after LM was demonstrated in early versus late ambulation.