Increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria

Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

“…Astrocytes and activated immune cells are potential sources for the observed increased glutamate levels in acute MS lesions (Frigo et al, 2012). Even in neurodegenerative conditions caused by infections with the protozoan parasites Plasmodium falciparum or Toxoplasma gondii, increased cerebral spinal fluid glutamate concentrations have been measured, which possibly represent a major cause of cerebral malaria and toxoplasmosis-associated brain damage (Miranda et al, 2010;David et al, 2016). The evidence for elevated extracellular levels of glutamate in PD is sparse, although in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, glutamate concentrations in the substantia nigra were significantly increased (Meredith et al, 2009).…”

Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents

“…From the 1990s, understanding the disruptions that can cause this increase has been an intense focus of interest in the pathophysiology of neurodegenerative diseases. These conditions (Table 1) came to include AD [72], PD [73], Huntington’s disease [74], amyotropic lateral sclerosis [75], stroke [76], viral encephelitides [77, 78], septic encephalopathy [79], defective post-operative cognition [80], post-irradiation brain function [81], pain [82, 83], bacterial meningitis [84], epileptic seizures [85], human immunodeficiency virus (HIV) dementia [86], cerebral malaria [87], and TBI [88–90]. In addition, the key studies of Jourdain and co-workers [91] convincingly combined functional and ultrastructural evidence to argue the case for glutamate from astrocytes being a key player in physiological control of synaptic strength.…”

“…Through the last decade, DON has been a useful, albeit often toxic [224], experimental tool to demonstrate that glutamate-mediated excitotoxicity is a significant component of the pathogenesis of various neurodegenerative states, including brain ischemia [225]. Cerebral glutamate homeostasis is disrupted in mouse models of both the neurological sequelae of Sindbis virus infection [226] and malarial encephalopathy caused by Plasmodium berghei ANKA [87], and DON has been successfully used therapeutically in experimental versions of both conditions [215, 227]. It has also been useful in an in vitro HIV dementia model [228] and in both in vitro and ex vivo experimental autoimmune encephalitis, a mouse model of multiple sclerosis [229].…”

Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases

“…Notably, through its neutralization with etanercept , TNF has been incriminated in a rat model of cerebral palsy (Aden et al ., ). Moreover, glutamate excitotoxicity, a TNF‐induced phenomenon we have explained (Clark and Vissel, ) through the combined effects of this cytokine enhancing glutaminase (Takeuchi et al ., ) and inhibiting glutamate re‐uptake proteins (Fine et al ., ; Carmen et al ., ), has been documented in a mouse model of cerebral malaria (Miranda et al ., ). This model has recently been reported to be highly sensitive to treatment with the glutamine analogue 6‐diazo‐5‐oxo‐L‐norleucine, a glutaminase inhibitor (Gordon et al ., ).…”