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Ceramide
Is Overproduced in HIV Dementia
By
Will Boggs, MD
Overproduction
of ceramide, a lipid associated with cellular dysfunction and apoptosis
in HIV dementia, according to a report in the February issue of
the Annals of Neurology. Therefore, agents that target the
metabolic pathways involved in the overproduction of ceramide may
have therapeutic potential.
Neurotoxic
HIV-1 proteins increase oxidative stress, the authors explain, and
oxidative stress can increase the generation of ceramide, which,
in turn, can sensitize neurons to excitotoxic damage and promote
apoptosis.
Dr.
Norman J. Haughey from Johns Hopkins University School of Medicine,
Baltimore, Maryland and colleagues sought to determine whether sphingolipid
metabolism, including the generation of ceramide, is dysregulated
in brain tissue and cerebrospinal fluid (CSF) of patients with HIV
dementia.
The
researchers found evidence of microglial activation, increased lipid
peroxidation, and altered sphingolipids in brain tissue from AIDS
patients with dementia.
Sphingomyelin
levels were increased in the medial frontal gyrus, cerebellum, and
CSF, the report indicates, as were ceramide levels, particularly
in patients with moderate to severe HIV dementia.
Exposure
of cultured hippocampal neurons to increased levels of sphingomyelins
or ceramides induced neuronal death in a concentration-dependent
manner, the authors report. GW4869 (a sphingomyelinase inhibitor)
and ISP-1 (an agent that depletes sphingomyelin and ceramide levels
in cultured neurons) significantly protected cultured neurons against
the toxicity of HIV proteins.
"Our
data suggest that metabolic pathways leading to the overproduction
of ceramide may present two additional targets for therapeutic intervention,"
the investigators conclude. "Blocking or modifying these points
of convergence in inflammatory and HIV protein-induced apoptotic
pathways are attractive approaches for the treatment of HIV dementia."
"Although
interventions designed to protect neurons by modulating or antagonizing
calcium-permeable membrane receptors work well in tissue culture,
in clinical trials these compounds have had limited success,"
Dr. Haughey told Reuters Health. "Therapies designed to modulate
the lipid environment in brain may be a more efficacious approach
to protect neural cells from injury and death."
"ISP-1
and GW4869 are both potentially clinically useful compounds,"
Dr. Haughey said.
"We
are currently looking at the relationship of dysfunctions in sphingolipid
(including ceramide) and sterol metabolism to the progression of
dementia in several HIV-infected cohorts," Dr. Haughey added.
03/12/04
Ann
Neurol 2004;55: 257-267.
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