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(Stroke. 2001;32:1234-a.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Glutamate, Interleukin-6, and Early Clinical Worsening in Patients With Acute Stroke
ICMSN, IDIBAPS, Hospital Clinic, Barcelona, Spain
Neurology Service, Hospital Clinico Universitario, Santiago de Compostela, Spain
Neurology Service, Hospital Universitario Doctor Josep Trueta, Girona, Spain
To the Editor:
We appreciate Dr Christensen’s interest in our work, recently published in Stroke.1 As we stated in the Subjects and Methods section of that article, the 231 patients analyzed in our study were selected form a larger cohort of 249 patients admitted consecutively between October 1992 and December 1996. Shrewdly, Christensen correctly guesses that this larger cohort includes the 128 patients that supported our report on glutamate excitotoxicity in acute ischemic stroke.2 Therefore, this larger series gives additional ground and further credit to the role of glutamate and IL-6 on neurological deterioration in patients with ischemic stroke.
The concentrations of glutamate in plasma
(309.6±64.8 versus 106.3±49.3 µmol/L;
P<0.0001) and CSF (13.3±3.8
versus 6.4±4.2 µmol/L;
P<0.0001) were significantly
higher in patients with clinical deterioration than in patients who
remained stable or improved during the first 48 hours. Glutamate and
IL-6 levels were positively correlated in samples of both plasma
(Spearman coefficient 0.66,
P<0.001) and cerebrospinal
fluid (CSF) (Spearman coefficient 0.49,
P<0.001). As shown in the
Table
, variables that remained independently
associated with early clinical deterioration on
multivariate analysis included IL-6 >21.5
pg/mL in plasma or >6.3 pg/mL in CSF, glutamate >200 µmol/L in
plasma or >8.2 µmol/L in CSF, admission Canadian Stroke Scale score,
and serum glucose.
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As pointed out by Dr Christensen, IL-6 has complex mechanisms of action that at present are not clearly understood. While we and others3 suggest proinflammatory properties in acute stroke, a recent article reported in this journal4 disputed these conclusions and found deleterious properties of IL-6. In this study, infarct size and neurological function at 24 hours were not different in animals deficient in IL-6 after transient cerebral ischemia.4 Moreover, other animal models5 have shown that the local infusion of IL-6 attenuated the neurotoxic effects of NMDA in striatal cholinergic neurons, thus suggesting neuroprotective rather than proinflammatory actions.
Glutamate and IL-6-disclosed related effects in our patients, in agreement with the overlap observed between inflammatory and excitotoxic pathways in experimental models. The increased expression of cytokine genes after injection of NMDA suggested that overactivation of NMDA receptor is one of the main stimuli to cytokine gene transcription in the ischemic brain.6 IL-1 may interact with AMPA and NMDA receptors in the striatum to stimulate cortical pathways that lead to neuronal death, probably through glutamate release.7 In contrast, IL-1 receptor antagonist blocks cerebral damage caused by both NMDA and AMPA receptor activation.7 Finally, IL-10 prevents apoptotic changes induced in response to glutamate release. Cortical cultures obtained in IL-10 knockout mice are more vulnerable to NMDA injury in vitro, whereas the administration of IL-10 to this culture prevents neuronal death induced by excitotoxic stimuli.8 9
In summary, our results suggest that glutamate and IL-6 are important and independent contributors to neurological deterioration in patients with acute stroke. However, additional studies will be needed to clarify the mechanisms underlying neurological worsening, including the interaction between IL-6 and glutamate. Hopefully, this deeper understanding will result in more effective therapeutic strategies for this devastating condition.
References
1.
Vila N,
Castillo J, Dávalos A, Chamorro A. Proinflammatory cytokines
and early neurological worsening in ischemic stroke.
Stroke. 2000;31:2325–2329.
2. Castillo J, Dávalos A, Noya M. Progression of ischaemic stroke and excitotoxic amino acids. Lancet. 1997;349:79–83.[Medline] [Order article via Infotrieve]
3. Clark W, Rinker L, Lessov N, Hazel K, Eckestein F. Time course of IL-6 expression in experimental CNS ischemia. Neurol Res. 1999;21:287–292.[Medline] [Order article via Infotrieve]
4.
Clark W,
Rinker L, Lessov N, Hazel K, Hill JK, Stenzel-Poore M, Eckestein F.
Lack of interleukin-6 expression is not protective against focal
central nervous system ischemia.
Stroke. 2000;31:1715–1720.
5. Toulmond S, Vige X, Fage D, Benavides J. Local infusion of interleukin-6 attenuated the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci Lett. 1992;144:49–52.[Medline] [Order article via Infotrieve]
6.
Szaflarski
J, Burtrum D, Silverstein FS. Cerebral hypoxia-ischemia
stimulates cytokine expression in perinatal rats.
Stroke. 1995;26:1093–1100.
7. Relton JK, Rothwell NJ. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull. 1992;29:243–246.[Medline] [Order article via Infotrieve]
8. Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E. Interleukin-10 modulates neuronal thresold of vulnerability to ischemic damage. Eur J Neurosci. 2000;12:2265–2272.[Medline] [Order article via Infotrieve]
9. Castillo J, Dávalos A, Noya M. Aggravation of acute ischemic stroke by hyperthermia is related to an excitatory mechanism. Cerebrovasc Dis. 1999;9:22–27.[Medline] [Order article via Infotrieve]
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