Increased Plasma Glutamate in Stroke Patients Might Be Linked to Altered Platelet Release and Uptake

Abstract

Experimental studies have shown the role of excitotoxicity in the pathogenesis of ischemic brain lesions, and glutamate levels have been found to be elevated in CSF and plasma from patients, early after stroke. In this study, we investigated whether platelets could be involved in the mechanism of altered plasma glutamate levels after stroke. Forty four patients, from 6 hours to 9 months after ischemic stroke, 15 age-related healthy controls and 15 controls with stroke risk factors or previous transient ischemic attack were enrolled. Glutamate plasma levels, platelet glutamate release after aggregation and platelet glutamate uptake were assessed. Plasma glutamate levels were increased up to 15 days after the ischemic event in stroke patients, and the levels at day 3 were inversely correlated with the neurologic improvement between day 3 and 15. Ex vivo platelet glutamate release was decreased by 70% in stroke patients, suggesting previous in vivo platelet activation. Moreover, platelet glutamate uptake in these patients was decreased by 75% up to 15 days and was still reduced 90 days after stroke. Our data show a prolonged increase of glutamate in plasma after stroke, which might presumably be linked to altered platelet functions, such as excessive release of the amino acid or impaired uptake.

The potential role of glutamate in the current diabetes epidemic

“…Interestingly, in both these conditions, increased glutamate levels are inversely correlated with lymphocytic activity [136] and hyperglutamatemia has been implicated in the pathogenesis of immunosuppression [136][137][138]. Hyperglutamatemia is common in neurodegenerative diseases and in particular in stroke patients [139][140][141] where it has been ascribed to an increased release of glutamate by the activated platelets [139,140]. In multiple sclerosis, increased glutamate levels have been associated with a mutation of the glutamate transporter GLT1 [142].…”

“…Amyotrophic lateral sclerosis [143][144][145], Parkinson's disease [146], epilepsy [147], autism [148], migraine [149], and depression [150] are also associated with increased circulating glutamate levels. Interestingly, hyperglutamatemia has been shown also in patients with rheumatoid arthritis [151] where, as in stroke patients, it has been related to the increased release of glutamate by the activated platelets [139,140]. The relevance of the hyperglutamatemia observed under different pathological conditions to disease manifestation and natural history is not always clear but indicates an important area of investigation.…”

“…T cells may directly impair BBB function and induce an encephalomyelitis-like disease [185]. The impaired BBB function might increase the load of glutamate in the CNS [185] and worsen neurotoxicity that, in turn, might increase plasma glutamate levels [139][140][141][142][143][144][145][146][147]. Hyperglutamatemia affects the immune system [136][137][138]186] and might also exert a suppressive function on regulatory T cells as glutamate decreases Interleukin-10 secretion by peripheral blood lymphocytes of subjects with autoimmune thyroiditis [187].…”

Ceftriaxone Preserves Glutamate Transporters and Prevents Intermittent Hypoxia-Induced Vulnerability to Brain Excitotoxic Injury

“…The role of excitotoxicity in the pathogenesis of ischemic brain disease has been widely reported [10] and elevated glutamate levels have been found in plasma and in cerebrospinal fluid of stroke patients [11]. Acute ischemia, as occurs during stroke, induces the release of glutamate and down-regulates glutamate transporter expression, critical to the regulation of intrasynaptic glutamate [11], [12], [13].…”

Emerging evidence for a similar role of glutamate receptors in the nervous and immune systems

“…Thus, normal glutamate concentration in human blood ranges from 70 to 100 lM but may increase to 300 lM or more as a result of oxidative stress (Aliprandi et al 2005). Metabolites derived from cysteine and methionine metabolism, namely HC, homocysteic acid (HCA), cysteine sulfinic acid (CSA) and homocysteine sulfinic acid, are potentially toxic circulatory compounds.…”