More on NMDA
They left NMDA out of the picture. I believe it belongs between glutamate release and resulting "stuff."http://www.scielo.br/scielo.php?pid=S01 ... ci_arttext
It is well known that one of the main effects of the stress response is the release of large quantities of excitatory amino acids, such as aspartate and glutamate, in different brain areas, an effect occurring rapidly after the onset of stress (20 min to 2 h) (3).
Released glutamate can bind to different receptors; the main one being the N-methyl-D-aspartate (NMDA) subtype, whose activation causes the mobilization of free cytosolic calcium. Excess in the intracellular calcium concentration over-activates certain calcium-dependent enzymes resulting in the generation of oxygen radicals, protein misfolding and cytoskeletal damage (14), constituting the process known as excitotoxicity.
Trying to go further in the sequence of events initiated by stress exposure, we also investigated the possible influence of glutamate in the release of TNF-α by blocking the NMDA glutamate receptor with the specific non-competitive compound MK-801 (dizocilpine). Interestingly, NMDA blockade not only decreases stress-induced activity and expression of TACE, but also its constitutive expression, as well as TNF-α levels (27). Taken together, these results demonstrate a crucial role for glutamate in the initiation of a response that shares certain features with the inflammatory processes. These results highlight a direct central regulatory effect of stress-induced neuroinflammation to be added to the entry of cytokines from outside the brain.
NFκB is a transcription factor widely expressed in the CNS. It consists of homodimers or heterodimers of a family of structurally related proteins. The most commonly found type is the heterodimer composed of a p65 (RelA) and a p50 subunit. This dimer can also bind to a third protein called IκB, which inactivates NFκB. The activation of this transcription factor comprises the sequential activation of different enzyme complexes such as NFκB-induced kinase (NIK), which, in turn, activates IκB kinase (IKK) that catalyzes the phosphorylation of two serines in NFκB. This constitutes the signal for the degradation of IκB. Once free of the inhibitory subunit, NFκB can enter the nucleus where it binds to specific κB DNA consensus sequences in the enhancer region of a variety of κB-responsive genes, some of which are involved in oxidative-nitrosative damage (29).
Stress activates NFκB in brain cells as soon as 4 h after the onset of stress in rats (reviewed in Ref. 19) and potentiates the activity of this transcription factor in the frontal cortex and hippocampus of rats under endotoxic shock (induced by LPS) (9). This activation of NFκB after stress was confirmed in experiments with humans and transgenic mice subjected to psychological or immobilization stress (30).
Many stimuli such as viral and bacterial infection, glutamate, UV light, ionizing radiation, free radicals, and cytokines activate NFκB (29). One of these activators is TNF-α (31). The implication of TACE and TNF-α in stress-induced activation of NFkB was confirmed after finding that the pharmacological inhibition of TACE also blocked the stress-induced activation of NFκB (27).
Additionally, the essential role of NMDA activation as a trigger factor in this process is of particular interest, since blockade of this receptor decreases NFκB translocation induced by LPS (9), and also decreases stress-induced TACE activation and TNF-α release (19).
We will now examine the consequences of the activation of such a transcription factor, leading to the expression of several responsive genes such as those involved in oxidative/nitrosative products.
NFκB-related oxidative/nitrosative products in stress
Some of the genes responsive to NFκB are oxidative/nitrosative sources. These include inducible nitric oxide synthase (iNOS, NOS-2) and cyclooxygenase-2 (COX-2).
iNOS. Nitric oxide (NO) is synthesized from L-arginine by the enzymes NO synthases: endothelial, neuronal and an isoform expressed during inflammatory reactions (iNOS). iNOS is an enzyme expressed after exposure of cells to several noxious agents such as cytokines or LPS (32). This NOS isoenzyme mediates cytotoxicity in many cell systems, mainly because of the oxidative/nitrosative effects produced by extensive and prolonged release of NO, which finally lead to a production of other oxidant species such as peroxynitrite (33).
Evidence has been presented for the role of NO in some pathological processes in the CNS. Indeed, the excessive generation of NO has been demonstrated in epilepsy, hypoxic-ischemic damage and neurodegenerative disorders including Alzheimer's and Parkinson's diseases and Huntington's corea (32).
It has been reported that exposure to stress results in increased NO production in the brain and periphery. A similar transient stimulation of NO release also occurs in plasma of humans subjected to stress (reviewed in Ref. 19). This systemic release of NO may offset the vasoconstrictor and pro-aggregatory effects of stress hormones and mediators during the first stages of the stress response.
Immobilization stress increases brain iNOS activity and expression as soon as 6 h after the onset of stress (34), and longer periods of stress produce higher levels of iNOS expression and activity (reviewed in Ref. 19). The detrimental effects of the long-term stress induction of iNOS include accumulation of membrane aldehyde products (peroxidation products), disruption of blood brain barrier and mitochondrial impairment (19). Pharmacological data obtained using specific inhibitors of iNOS support the conclusion of the participation of iNOS in stress-induced damage. It is unclear whether NO per se is the effector molecule of neuronal damage. A persistent elevation of NO levels can result in generation of a potent oxidant, peroxynitrite (ONOO-) from superoxide and NO. Peroxynitrite is a tissue-damaging agent that acts by the initiation of lipid peroxidation, oxidation of sulfhydryl groups and nitrosation of tyrosine-containing molecules. The huge accumulation of NO and over-expression of iNOS observed in the brain during chronic stress probably leads to the production of reactive oxygen or nitrogen species such as peroxynitrite (19).
iNOS induction in stress depends on NFκB activation. This was supported by the use of an inhibitor of NFκB activation such as pyrrolidine dithiocarbamate, which decreased the activity and expression of iNOS in stressed animals (34).
Pharmacological experiments were carried out to study the possibility that cytokines and excitatory amino acids account for the stress-induced activation of iNOS. Indeed, specific blockers of the NMDA receptor of glutamate (MK-801) or TACE inhibitors (BB1101) partially inhibit the stress-induced iNOS expression and activation (25).
On the other hand, the COX pathway has also been implicated in stress-induced brain damage. COX-2 is induced in stress and has been involved in the damage associated with this condition. According to its condition of inducible enzyme, and similarly to iNOS, the promoter of the immediate-early gene COX-2 depends on the activation of NFκB in stress. Both enzymatic sources of oxidative mediators in the brain depend on the activation of the NMDA type of glutamate receptor, and, in the case of iNOS, its activation also depends on the release of TNF-α.
I think the difference in how this affects people with RRMS and SPMS/PPMS is here...could be wrong though. This is pretty new to me.
Energy deficiency and dysfunction of Na,K-ATPase are common consequences of many pathological insults and stress. Glutamate through cyclic guanosine monophosphate (GMP) and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate α2/3-Na,K-ATPase activity in the CNS (58). Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. Studies in rats suggest that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate-positive modulation of cerebellar α2/3-Na,K-ATPase is linked to a defective PKG signaling pathway (59). The loss of the ability of α2/3-Na,K-ATPase to respond to glutamate through a cyclic GMP-PKG cascade could be a failure in an important mechanism for rectifying ionic disturbances that may be present in aging processes and may predispose to or potentiate an effect of stress in the manifestation of age-related degenerative disorders. In fact, chronic predictable and unpredictable stress decrease the neuronal Na,K-ATPase activity and high levels of glucocorticoid have been detected in 24-month-old rats (Munhoz CD, Scavone C, unpublished results), which could induce a further reduction of ATP levels during a neurological insult. It is interesting to note that the aging process (30-month-old animals) induces up-regulation in constitutive NFκB binding activity in the frontal cortex, which in the presence of glucocorticoid levels could potentiate LPS-induced NFκB activation and an increase in mRNA of proinflammatory genes (9). In addition, rats with increased HPA reactivity induced by prenatal stress or by the absence of neonatal handling show an early decline of cognitive functions associated with the hippocampus, as well as increased propensity to self-administer drugs such as amphetamine and cocaine (55). In addition, exposure to both chronic restraint and unpredictable stress increased cocaine-induced locomotion and basal corticosterone plasma levels and chronic unpredictable stress also displayed the largest locomotor response following a challenge dose with cocaine compared with control and chronic restraint stress groups (60). Drug abuse is associated with changes in brain function and neurodegenerative processes, which, for some drugs, have been shown to be associated with the induction of apoptotic/necrotic cell death (Lepsch LB, Munhoz CD, Kawamoto EM, Lima LS, Scavone C, unpublished results). Thus, life-long patterns of HPA function are probably important to determine the susceptibility of the body to stress or insults during the aging process.