AIDS:
16 August 2002 - Volume 16 - Issue 12 - pp 1691-1692
Correspondence
Glutamate may be the soluble cerebrospinal fluid factor that induces calcium dysregulation in cultured astrocytes in HIV dementia
Tremolizzo, Lucio; Aliprandi, Angelo; Longoni, Marco; Stanzani, Lorenzo; Ferrarese, Carlo
Author Information
Department of Neurology, DNTB, University of Milano-Bicocca, Monza, Italy.
Received: 15 February 2002; accepted: 28 February 2002.
In their recent report, Koller and colleagues [1] demonstrated that soluble factors in the cerebrospinal fluid (CSF) of patients with AIDS dementia complex (ADC) induced dysregulation of calcium homeostasis in rat cultured cortical astrocytes. Moreover, they claimed that their test allowed them to identify clearly the patients with dementia and that it could be useful in the diagnosis of the preclinical stages of the disease. The nature of the substances involved is still to be clarified, but the authors suggested that several factors, including viral proteins GP120 and TAT, cytokines and quinolinic acid, which have been found to be increased in the CSF from HIV dementia patients, might be involved in calcium dysregulation.
Recently, we reported [2] increased glutamate levels in the CSF of patients with ADC, a result that strongly supports a role for excitotoxicity in this pathology [3]. A fivefold increase in glutamate CSF levels was shown in ADC patients compared with HIV patients without dementia, HIV-seronegative demented patients and healthy controls; moreover a correlation between glutamate levels and cognitive decline (assessed by Memorial Sloan Scale, MSK) and brain atrophy (assessed by computed tomography scan) was demonstrated.
Glutamate is a well-known neurotoxin, which is able to increase cell calcium conductance [4], eventually leading to a further release of glutamate. In their experimental paradigm, Koller and colleagues measured glutamate-induced calcium uptake in cultured astrocytes after pre-incubation with CSF from patients and controls. We suggest that the reduction in the glutamate-mediated calcium response reported in this experimental set might be caused by the pre-exposure of cultures to the high levels of this amino acid present in the CSF of ADC patients. Indeed, basal intracellular calcium levels were higher in cell cultures treated with the CSF of ADC patients than in the CSF from controls, although reaching similar levels after glutamate exposure, with lower glutamate-induced calcium influx. This suggests that the reduced calcium increase might be caused by previous influx of the cation through glutamate-stimulated N-methyl-d-aspartate receptors, with the consequent exhaustion of cell buffering systems and a reduction of calcium levels in the culture medium, rather than by direct impairment of calcium homeostasis. Furthermore, pre-incubation with high glutamate levels has been shown to upregulate the uptake of the amino acid in astrocytes [5]. As a result, pre-treated cultures could be less sensitive to further glutamate stimulation, as transport systems would be more effective than in naive cultures in lowering the extracellular concentration of the neurotransmitter.
The role of glutamate as an important mediator of neurotoxicity in ADC is further stressed by the identification by Jiang and colleagues [6] of this amino acid as the key toxic factor present in the medium from activated HIV-1-infected macrophages.
The effect of other hypothetical neurotoxins (virotoxins or cytokines) could be mediated by their ability to stimulate the release or inhibit the uptake of the amino acid, thus increasing its concentration in extracellular fluids. Such a mechanism has already been documented for both Gp120 [7] and Tat [8], for the pro-inflammatory cytokine TNF-α [9], which was found to be increased in the CSF of ADC patients [10], and for eicosanoids [11].
The lack of correlation, shown by Koller et al., between the calcium response in astrocytes and the CSF parameters (including the CSF : serum albumin ratio) confirms our hypothesis of a CNS production of glutamate, rather than a spill-over from blood, as previously suggested [12].
Therefore, CSF glutamate may be proposed as a more direct biological marker for ADC, and could also be employed for the preclinical diagnosis of the disease, which may allow an earlier therapeutic intervention.
An improved knowledge of the neuronal death pathway will aid in the design of a more specific drug for ADC (such as memantine, a non-competitive N-methyl-d-aspartate antagonist), a target of extreme importance in the era of the prolonged survival of HIV-positive patients.
Lucio Tremolizzo
Angelo Aliprandi
Marco Longoni
Lorenzo Stanzani
Carlo Ferrarese
References
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© 2002 Lippincott Williams & Wilkins, Inc.