Morphine reduces mortality in mice following ocular infection with HSV-1.

To determine the effect of chronic opioid treatment on mice infected with herpes simplex virus (HSV-1), female ICR mice were administered saline or morphine (25 mg/kg) subcutaneously (s.c.) 3 X /day and infected five days later via corneal scarification and inoculation with 150-210 plaque forming units of HSV-1. Mice deprived of morphine succumbed following infection faster than morphine- or saline-maintained mice, and morphine-maintained mice had a higher cumulative survival than either saline-maintained or morphine-deprived mice. There was no significant difference in cytokine mRNA or protein levels by RT-PCR and ELISA, respectively, in the eyes, trigeminal ganglia, cerebellum, or brain stem, comparing morphine-maintained to saline-treated mice. Similarly, there were no differences in the viral load in the eyes and trigeminal ganglia during the acute infection comparing these two groups assayed three and six days post-infection. While there were no differences in the expression of viral transcripts in the eyes and trigeminal ganglia during the acute infection, HSV-1 infected cell polypeptide 27 expression was reduced in the brain stem of morphine-maintained mice. Collectively, the results suggest that mice maintained on morphine antagonize the spread of HSV-1 in the central nervous system and thus, reduce the incidence of viral-induced encephalitis.

Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels.

Cerebrovascular deposits of amyloid (cerebral amyloid angiopathy, or CAA) are generally asymptomatic, but in advanced cases, they can lead to vessel rupture and hemorrhage. The process of progression in CAA was studied by comparison of postmortem brains with asymptomatic ("mild") CAA to brains with the form of the disease associated with hemorrhage ("severe CAA"). Cortical and meningeal vessels were immunostained for beta-amyloid and examined by confocal microscopy and by systematic quantitative sampling. We focused on 2 quantitative parameters: the proportion of vessels affected by amyloid (a measure of amyloid seeding of vessels) and the amount of amyloid per affected vessel (a measure of growth of existing lesions). Surprisingly, there was no difference between the proportion of affected cortical vessels in mild and severe CAA (0.29 vs 0.32, p = 0.65), but rather an increase in the area of the 40 amino acid form of beta-amyloid per affected cortical vessel (198.5 +/- 38.7 vs 455.8 +/- 100.9 microm2/vessel, p < 0.007). Increasing doses (from 0 to 1 to 2 copies) of the apolipoprotein E epsilon4 allele were also associated with greater amyloid per vessel without change in the proportion of affected vessels within each class of CAA severity. These findings suggest that progression from asymptomatic to advanced CAA reflects progressive accumulation of amyloid in vessels previously seeded with amyloid, and that this process is selectively enhanced by apolipoprotein E epsilon4.

Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.

Recent data have implicated apolipoprotein E (apoE) in neuritic outgrowth, synaptic stability, and Alzheimer's disease; these data led us to examine the normal role of apoE-containing lipoproteins in the central nervous system (CNS). We isolated lipoproteins from human cerebrospinal fluid (CSF) in order to examine their composition and potential functions. CSF particles were composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol. ApoE3 formed homodimers and heterodimers with apoA-II, while apoE4, as expected, was monomeric. We addressed the function of CSF lipoproteins with assays of cholesterol efflux and cholesterol influx. CSF lipoproteins decreased intracellular levels of cholesterol in cholesterol-loaded fibroblasts, suggesting these particles can act to remove excess lipids from cells. CSF lipoproteins competed for 125I-labeled LDL degradation by fibroblasts, suggesting they can also interact with the LDL receptor. Furthermore, CSF lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture. Together, these data support a model of CSF lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage.