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Elevated central nervous system prostaglandins in human immunodeficiency virusЧassociated dementia.

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Elevated Central Nervous Svstem
Prostaglandins in Human Immunodeficiency
Virus-associated Dementia
Diane E. Griffin, MD, PhD, Steven L. Wesselingh, BMBS, PhD, and Justin C. McArthur, MBBS, MPH
The dementia associated with human immunodeficiency virus (HIV) is poorly understood, Dementia is accompanied
by infection and activation of macrophage lineage cells in the brain and production of toxic products by these cells
has been postulated to play a role in the pathogenesis of dementia. Eicosanoids are potential products of activated
macrophages that can mediate cell injury. We measured the levels of prostaglandin E, in the cerebrospinal fluid of
HIV-positive individuals with dementia and/or myelopathy and compared these levels with those of HIV-negative
patients with other neurological diseases and HIV-positive patients without dementia. Cerebrospinal fluid prostaglandin E, levels were increased in dementia. This increase was associated with severity of dementia and correlated with
cerebrospinal fluid levels of neopterin and &-microglobulin. Prostaglandins F,, and thromboxane B,, additional
products of the cyclooxygenase pathway of arachidonic acid metabolism, were also elevated in dementia, but leukotriene C4, a product of the lipoxygenase pathway was not. Since synthesis of prostaglandins is regulated in part by
the levels of inducible forms of cyclooxygenase, we measured the levels of cyclooxygenase-1 and 2 mRNAs in the
brains of HIV-positive individuals with and without dementia by reverse transcriptase polymerase chain reaction.
Levels of intact cyclooxygenase-1 mRNA were higher in the brains of demented individuals, but this did not reach
statistical significance. These data demonstrate that prostaglandins are increased in the central nervous system in
HIV-associated dementia and may play a role in the development of neurological dysfunction.
Griffin DE, Wesselingh SL, McArthur JC. Elevated central nervous system prostaglandins in human
immunodeficiency virus-associated dementia. Ann Neurol 1994;15:592-597
Dementia is an important, but inadequately understood, complication of human immunodeficiency virus
(HIV) infection. Clinical evidence of neurological impairment correlates poorly with pathological changes
in the central nervous system (CNS) at autopsy [1-31.
Certain abnormalities do correlate with dementia and
potentially provide clues to the pathogenesis of neurological dysfunction. These clues consist of increased
levels of neopterin [4}, quinolinic acid { S ] , and PLmicroglobulin [GI in cerebrospinal fluid (CSF) and increased levels of tumor necrosis factor-a (TNF-a)
mRNA combined with decreased levels of interleukin-4 (IL-4) mRNA in the brain parenchyma [7}. Neopterin, quinolinic acid, p,-microglobulin, and TNF-a
are produced by cells of the monocyteimacrophage lineage, and immunocytochemical staining of CNS tissue
has localized increased TNF-a and P,-microglobulin
protein primarily to microglial cells and perivascular
macrophages [S, 91. Therefore, it appears likely that
macrophage lineage cells within the CNS are activated
and may participate in the development of neural dysfunction in HIV infection {lo]. Low levels of IL-lP
mRNA C71 and failure to consistently stain microglial
cells for IL-1 [S] suggest that the activation of macrophages is selective.
Additional important products of macrophages result from the hydrolysis of membrane phospholipids.
Phospholipase A, releases arachidonic acid, which can
be oxidized by specific intracellular enzymes to form a
variety of biologically active eicosanoids (Fig 1). The
lipids in macrophages are highly enriched in arachidonic acid { 111. Products of arachidonic acid metabolism that are active as extracellular mediators include
the prostaglandin (PG) products of the cyclooxygenase
pathway and the leukotriene (LT) products of the lipoxygenase pathway 1121. There are reasons to postulate that eicosanoids may be involved in HIV-induced
CNS diseases based on in vitro studies. H I V gp120
increases synthesis of thromboxane B, (TxB2),PGF,,,
LTC4, and LTB, by human peripheral blood monocytes as a consequence of binding to CD4 [ 131. Cultivation of HIV-infected monocytes with glial cells stimulates synthesis of LTB,, LTD,, and platelet-activating
factor leading to injury of neurons present in the cul-
Departmenrs of Neurology and Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD.
Address correspondence to Dr Griffin, Meyer 6-181, Johns Hopkins
Hospital, 600 North Wolfe Street, Baltimore, MD 21287.
Received Jun 21, 1993, and in revised form Aug 20 and Sep 24
Accepted for publication Oct 6, 1993.
592 Copyright 0 1994 by the American Neurologicdl Association
HIV-seronegative patients with other noninflammatory neurological diseases (amyotrophic lateral sclerosis, Alzheimer’s
dementia, etc). CSF samples were frozen at -20°C or
- 70°C until analysis.
Cell membrane Phospholipids-20:4
Phospholipase A2
Arachidonic Acid
CyclooxygenaseJ
wpoxygenase
Prostaglandin 6 2
5-HPETE 12-HPETE
Cyc/ooxygeilasel
‘
I
Leukplriene A
Tissue Samples
Subcortical white matter from the right frontal lobe was obtained at autopsy from 11 seropositive individuals with HIVassociated dementia (mean CD4, 30.6 5 5.4), 5 HIVseropositive individuals with acquired immunodeficiency
syndrome (AIDS) but without dementia (mean CD4, 22 ?
4.3), and 2 HIV-seropositive individuals without an AIDSdefining illness (CD4 counts, 1,764 and 171). Tissue was
stored at - 70°C until R N A was extracted.
P ostaglandin H2
Thrombpxaned
1 1-2
Prostadlandin D2
prostaglandin FZ$
\
Leukotriene D
1
Leukotriene E
Fig 1. Schematic diagram of the pathways of arachidonic acid
metabolism. CivcIed eicosanoidr were measured in thir study.
tures [14]. Based on these and other in vitro studies,
arachidonic acid metabolites have been postulated to
play a major role in the development of neurological
disease associated with HIV infection El5l.
To characterize further the features of macrophage
activation in the CNS during HIV infection and to
determine whether there is in vivo evidence for increased eicosanoid production in dementia, we have
measured CSF levels of eicosanoids and brain levels of
cyclooxygenase m W A in HIV-infected patients prospectively characterized for neurological slatus. We
have found elevations of products of the cyclooxygenase, but not the lipoxygenase, pathway of arachidonic
acid metabolism.
Methods
Patients
HIV-seropositive individuals came from the inpatient and
outpatient services of the Johns Hopkins Hospital and from
the Johns Hopkins University neuropsychological component of the Multicenter AIDS Cohort Study (MACS). The
MACS neuropsychological study includes longitudinal neurological and neuropsychological testing in combination with
directed physical examination, questionnaires, CSF analysis,
and, in some subjects, magnetic resonance imaging. It is described in detail elsewhere f 161. The definitional criteria for
dementia suggested by the American Academy of Neurology
were used C17). The severity of the dementia was scored
using the Memorial Sloan-Kettering criteria {IS]. Informed
consent was obtained from all individuals and the studies
were approved by the Joint Committee for Clinical Investigation of the Johns Hopkins Medical Inscitudons.
Ezcosanoid Assays
PGE, was measured by radioimmunoassay (NEN Research
Products, Wilmington, DE). PGF,,, TxB,, and LTCd were
measured by enzyme immunoassay (Cayman Chemical, Ann
Arbor, MI). All assays were performed using the standards
and instructions supplied by the manufacturers.
Cyclooxygenase mRNA Analysis
Tissue was homogenized in RNAsol-Stat 60 (Tel Test,
Friendswood, TX) and total cellular R N A recovered. The
RNA was then incubated with RNase-free DNase to remove
any contaminating genomic DNA. cDNA synthesis, polymerase chain reaction (PCR), and southern analysis of the
PCR products were performed as previously described {7].
The following previously published [ 19, 20) cyclooxygenase
(prostaglandin G/H synthase) gene-specific PCR primers
were used: hCox-1: 5’-lTCATGCCAAACCTCTTGC-3
(antisense) and 5’-GGAGACCATCAAGATTGTC-3’ (sense)
and hCox-2: 5‘-TTCAAATGAGATTGTGGGAAAATTGCT (sense) and 5 ’-AGATCATCTCTGCCTGAGTATC7T-3‘ (antisense). These primers cross introns and therefore avoid confusion of genomic D N A with mRNA.
Twenty-five cycles of amplification were used. The sequence
of the 32P-labeledinternal oligonucleotides used to probe the
PCR products were 5 ’-GAACTCCATGGCAATGCGGnGCGGTATTG-3’ for hCox-1 and 5’-ACGCTGTCTAGCCAGAGTITCACCGTA-3’ for hCox-2. The relative intensity of the bands on autoradiograms was measured by laser
scanning densitometry and the ratio of the density of each
band to the density of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) band determined (primers and probes
as previously described) { 71.Negative controls were included
at each step, i.e., LWA extraction, cDNA synthesis, and
PCR.
Cerebrospinal Fluid
A total of 305 CSF samples from 160 HIV-seropositive individuals were studied. CSF samples from HIV-seropositive
patients included 86 samples from 40 neurologically normal
individuals, 98 samples from 42 individuals with minor neurological or neuropsychological abnormalities (insufficient to
be classified as demented), 91 samples from 46 patients with
HIV-associated dementia, 12 samples from 12 patients with
myelopathy, and 18 samples from 10 patients with dementia
and myelopathy. In addition, there were 52 samples from
Statlrtical Anat‘yJis
PGE, data were log-transformed for analysis, and samples
without detectable levels were assigned a value of 0.7 pg/
ml (below the lower limits of detection). The groups were
compared using x’, analysis of variance with Scheffgs correction, or Student’s t test as appropriate. Data for levels of
mRNA were compared using Student’s two-tailed t test. Calculations were performed with STATVIEW software (Abacus
Concepts, Berkeley, CA).
Griffin et al: Prostaglandins in HIV-associated Dementia
593
Results
The primary eicosanoid product of macrophages is
PGE, Ell} and macrophages are activated in the CNS
in HIV infection [8, 91. Therefore, we first compared
levels of PGE, in CSF from HIV-seronegative patients
with noninflammatory neurological disease (OND) and
HIV-seropositive patients. Similar numbers of seronegative (5 3.8%) and seropositive (56.476) patients
had detectable CSF PGE,, but geometric mean levels
of PGE, were higher in the seropositive group (2.10 2
0.15 vs 1.70 k 0.22 pg/ml, p = 0.22). All HIV-seropositive patients had neurological assessment and were
grouped into those who were neurologically normal
(Nnl), those who were abnormal on neuropsychological testing ( N P + j, those who were demented, and
those with myelopathy. Seventy-two percent of the
combined patients with dementia and myelopathy had
detectable PGE, in CSF, while in the combined neurologically normal and NP + groups 46% had detectable
CSF PGE, (x2 = 21.8, p < 0.001). The geometric
mean levels of PGE, in CSF were significantly higher
in patients with dementia and myelopathy than in the
neurologically normal seropositive patients or in the
seronegative controls (Fig 2) ( p < 0.001).
To determine if changes in CSF PGE, were associated with length of infection, CSF samples were studied from a subgroup of 35 HIV-infected patients who
were not demented and whose seroconversion time
was known. No significant change was detected in CSF
PGE, over 6 years’ follow-up in these individuals.
To assess the influence of low CD4 counts on CSF
levels of PGE,, patients were grouped according to
CD4 counts (Fig 3). Patients with dementiaimyelopathy with either high (>500) or low ((200) numbers
of CD4 T cells had higher levels of PGE, than neurologically normal patients with comparable CD4 T-cell
counts. Approximately one-half of the demented patients were taking antiretroviral therapy at the time of
study, but this had no discernible effect on CSF PGE,
levels (3.68 2 0.97 pgiml in treated vs 2.99 -+ 0.52
in untreated, p = 0.3).
For demented patients the severity of cognitive dysfunction was determined using standard criteria [ 181
and patients were grouped into those with mild (MSK
l), moderate (MSK 2), and severe (MSK 3-4) dementia. CSF PGE, increased as severity of dementia increased (Fig 4), mild compared with severe ( p =
0.025j. Two other products of activated macrophages,
neopterin and P,-microglobulin, have also been associated with dementia (21, 22). Many of the demented
patients analyzed for this study had already been evaluated for levels of neopterin [4] and p,-microglobulin [6] in CSF. PGE, levels in CSF were strongly correlated with CSF levels of neopterin (n = 25,
r = 0.597, p = 0.0013) and p,-microglobuLn (n =
51, Y = 0.416, p = 0.0022). There was no correlation
with numbers of cells in CSF (n = 182, r = 0.007).
594 Annals of Neurology Vol 35 No 5 May 1994
100
.1
1
’
4.
k
HIV-OND
, NNI
NP+
Dem/MyelI
HIV+
Fig 2. Prostaglandin E , (PGE,) in the cerebvospinal&id of
human immunodeficiency virus (HIVj-seronegativepatients
with neurological disease (HIV-OND) and of HIV-seropositive
Myel = myelopathy
patients with (Dem = dementia 1.;
; 1 . C Dem t Myel [DemlMyel, +}) and without (Nnl =
neurnlogically normal; NP + = abnormal neuropsychological
testing) neurological disease. Bars denote the geometric means
and the boxes. the standard errors of the means f i r each group.
PGE, was signaficantly elevated in patients with dementia
and myelopathy (analysii of variance. p = 0.0001).
NNI+NP+
p<.ooo1
c
E
m
4
Q
p=.013
Y
N
w
3
2
2
1
<200
200-500
>500
CD4+ T cells/lil blood
Fig 3. Prostaglandin E, (PGE,) in cerebrospinalfluid of hum a n immunodeficienly virus-seropositi6e patients with (Dem
= dementia and Myel = myeloputhy) OY without (Nnl = nenrologically normal; NP + = abnormal neuropsychological testingj central nervous system disease grouped according to CD4
T-cell numbers. In each group demented patients butte higher
PGE, levels than nondemented patients.
Mild
Moderate
growth factors, and phorbol esters appear to modulate
prostaglandin synthesis by inducing cyclooxygenase
[24]. To determine whether cyclooxygenase mRNAs
were present in brain and whether gene expression
was altered in dementia, we examined RNAs from the
brains of 12 demented and 7 nondemented HIVinfected AIDS patients by semiquantitative reverse
transcription (RT)-PCR for cyclooxygenase-1 (intact
and spliced) and cyclooxygenase-2 mRNAs. Spliced
(300-kb PCR product) and intact (400-kb PCR product) hCox-1 and hCox-2 mRNAs were detected in all
brains. In the demented patients the unspliced hCox-1
mRNAs were approximately two times the levels in
the nondemented patients, but this difference did not
reach statistical significance (Table 2).
Severe
Severity of Dementia
Fig 4. Cerebro.rpinalj u i d prostaglandin E, levels in human zmmunodejicienry virus-seropositive Patients with dementia of
vatying severity. Mild = MSK 1; moderate = MSK 2: .were
= MSK 3 and 4.
To determine if other products of the cyclooxygenase or lipoxygenase pathways of arachidonic acid metabolism were increased in HIV-associated dementia,
PGF,,, TxB,, and LTC, were measured in subgroups
of neurologically normal and demented HIV-seropositive patients (Table 1). PGF,, and TxB,, products
of the cyclooxygenase pathway of arachidonic acid
metabolism, were both increased in demented patients,
while LTC,, a product of the lipoxygenase pathway,
was not increased compared with HIV-seropositive patients without neurological symptoms.
Cyclooxygenase possesses two enzymatic activities,
i.e., cyclooxygenase activity for conversion of arachidonic acid to PGG, and peroxidase activity for conversion of PGG, to PGH,. It is the major controlling
enzyme in prostanoid synthesis. Cyclooxygenase is inactivated during catalysis and control of enzyme levels
is primarily at the level of transcription 1231. Two inducible enzymes are recognized, cyclooxygenase-1 and
-2 [ZO]. In macrophages the activity of cyclooxygenase-1 is regulated in part by alternative splicing of the
mRNA to include or exclude exon 9 {19]. Cytokines,
Discussion
There are two major pathways of metabolism of arachidonic acid after intracellular release from membrane
phospholipids. Macrophages (and presumably microglia) under differing circumstances make either PGE, as
a product of the cyclooxygenase pathway or the leukotrienes LTC4,LTD,, and LTE4 as products of the lipoxygenase pathway. In addition, other cells in the CNS
can produce eicosanoids. Astrocytes can be induced to
produce PGE, [25], endothelial cells to produce PGD,
[26], and neurons PGF,, [27]. We have shown that at
least three different products of the cyclooxygenase
pathway, PGE,, PGF,,, and TxB, are increased in the
CSF of patients with HIV-associated dementia. This
occurs without a concomitant increase in LTC,, a product of the lipoxygenase pathway. PGE, levels increase
with progressive severity of dementia and correlate
with elevations of neopterin and P,-microglobulin in
CSF. rnRNAs encoding forms of cyclooxygenase inducible by inflammatory mediators are increased in the
brains of demented patients. We conclude that upregulation of cyclooxygenase activity in the CNS is associated with dementia of H IV infection.
Normal CSF contains undetectable to low levels of
most eicosanoids 128, 291. Eicosanoids are not stored
free in cells and the CNS removes them through a
saturable, probenecid-sensitive mechanism in the cho-
Table 1. Eicosanoids in Cerebrospinal Fluid of Human Immunodeficiency Virus Patients Without
Neurological Diseases and W i t h Dementia
Detectable Eicosanoid
Neurologically Normal
Dementia ( n
(n = 32)
Mean (Range)
=
34)
Mean (Range)
Eicosanoid
n
(pgiml)
n
(pgiml)
X’
P
Prostaglandin F,,
Thromboxane B,
Leukotriene C,
2
1
1
177 (160-193)
12.3
175
15
193 (17-680)
39.8 (8.8-200)
15
17.1
17.7
<0.001
14
1
0.3
<0.001
NS
Griffin et al: Prostaglandins in HIV-associated Dementia
595
Table 2. Relative Levels of Cycloox9genaJ-emRNA.i in the Subcortical White Matter of Human
lmmunodejciency Virus-Seropo.titive Patients With and Without Dementia
Cyclooxygenase-1
Intact
Patients
Demented
Nondemented
0.740
0.381
P
0.315
?
0.243 (SEM)
* 0.171
roid plexus {30]. Therefore, increased levels of eicosanoids in CSF reflect increased synthesis within the
CNS. The mRNAs for both cyclooxygenase-1 and -2
are present in brain. The source of increased PGE,
synthesis in the CNS is most likely to be infiltrating
macrophages or microglia, since these cells are known
to be activated in HIV-associated dementia and myelopathy {S, 91. However, rodent astrocytes can be
induced to produce PGE, as well as PGD, and TxB,
[25, 31). Since astrogliosis is common in HIVassociated dementia {S, 321, astrocytes may also contribute to this increase. Endothelial cells are a third
potentially important source of inducible prostaglandin
synthesis [20) in the CNS. The RT-PCR technique did
not allow us to distinguish whether the cyclooxygenase
pathway of arachidonic acid metabolism might be altered in a variety of CNS cell populations or in a single
type of cell capable of producing multiple prostanoids.
Eicosanoids are produced in response to membrane
receptor activation [33] and synthesis is dependent
both on release of arachidonic acid and on the levels
of the rate-limiting enzymes, cyclooxygenase and lipoxygenase. Receptor-mediated events that activate
phospholipase to release arachidonic acid probably also
determine the pathway by which it will be metabolized
[34} through transcriptional control of the levels of
cyclooxygenase and lipoxygenase. TNF-a increases
phospholipase A, activity in endothelial cells [35},
macrophages 1361, and fibroblasts [37], resulting in increased release of arachidonic acid {3S}. TNF-a also
increases the expression of cyclooxygenase-2 mRNA
{ 39} and increases the ratio of intact-to-spliced cyclooxygenase-1 mRNA [ 19). TNF-a expression is increased
in HIV-associated dementia { 7 ) and thus is likely to
contribute to increased eicosanoid synthesis in the
CNS. Several other mediators, including substance P,
also increase PGE, synthesis [40), but most appear to
act through the effects of TNF-a {41].
Macrophage synthesis of PGE, is known to be stimulated by antigen-antibody complexes, phagocytosis,
and lipopolysaccharide, while synthesis of leukotrienes
is stimulated by mast cell products released in response
to IgE receptor cross-linking {34}.Wahl and colleagues
[13] have reported that the HIV protein gp120 upregulates synthesis of both the cyclooxygenase products TxB, and PGF,, and the lipoxygenase products
596 Annals of Neurology Vol 35 No 5 May 1994
Spliced
C yclooxygenase-2
0.138
0.362 2 0.244
0.347 ? 0.170
2 0.081
0.134 2 0.074
>O. 5
>0.5
LTB, and LTC, by human monocytes through binding
CD4. Additional in vitro studies have shown that cocultures of HIV-infected monocytes with human glia
produced supernatant fluids that were toxic for neurons and contained a variety of leukotrienes C14). We
did not find increased LTC, in the CSF of demented
patients, suggesting that the lipoxygenase pathway may
not be activated in vivo as it can be in vitro.
Increases in CSF eicosanoids have been reported in
a variety of neurological diseases [28, 421. PGE, is
elevated in CNS infections, in multiple sclerosis, and
in psychiatric disorders [43). In cerebrovascular disease
PGF,, is the most consistently elevated eicosanoid
1441, while in hydrocephalus LTC, is increased [28).
The effects of increased levels of the products of
cyclooxygenase metabolism in the CNS are not clear.
PGE, increases cyclic AMP in cells with PGE, receptors resulting in a variety of effects including suppression of IL-1, IL-2, and interferon-y synthesis by
monocytes and lymphocytes {45, 461. In the CNS
eicosanoids affect neuronal function, regulate sleepwake cycles, and mediate IL-1- and TNF-induced fever 127,31, 47-49]. Therefore, it is possible that increased P G production in the CNS contributes to
some of the symptoms associated with HIV dementia.
This work was supported by grants AI76234, NS26643, and
RROO722 from the NIH. S.L.W. is the recipient of an N.H. and
M.R.C. Neal Hamilton Fairely Fellowship (Australia).
We thank John Humpal, Michael Rho, and Steven Choi for technical
assistance, Tish Nance-Sproson for help with the statistical analysis,
and Kimberley Collins for preparation of the manuscript.
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