Nitric oxide, cell bioenergetics and neurodegeneration

Abstract

Following stimulation of NMDA receptors, neurons transiently synthesize nitric oxide (NO) in a calcium/calmodulin-dependent manner through the activation of neuronal NO synthase. Nitric oxide acts as a messenger, activating soluble guanylyl cyclase and participating in the transduction signalling pathways involving cyclic GMP. Nitric oxide also binds to cytochrome c oxidase, and is able to inhibit cell respiration in a process that is reversible and in competition with oxygen. This action can also lead to the release of superoxide anion from the mitochondrial respiratory chain. Here, we discuss recent evidence that this mitochondrial interaction represents a molecular switch for cell signalling pathways involved in the control of physiological functions. These include superoxideor oxygen-dependent modulation of gene transcription, calcium-dependent cell signalling responses, changes in the mitochondrial membrane potential or AMP-activated protein kinase-dependent control of glycolysis. In pathophysiological conditions, such as brain ischaemia or neurological disorders, NO is formed excessively by NMDA receptor over-activation in neurons, or by inducible NO synthase from neighbouring glia (microglial cells and astrocytes). Elevated NO concentrations can then interact with superoxide anion, generated by the mitochondria or by other mechanisms, leading to the formation of the powerful oxidant species peroxynitrite. During pathological conditions activation of the NAD + -consuming enzyme poly(APD-ribose) polymerase-1 (PARP-1) is also a likely mechanism for NO-mediated energy failure and neurotoxicity. Activation of PARP-1 is, however, a repair process, which in milder forms of oxidative stress protects neurons from death. Thus, whilst NO plays a physiological role in neuronal cell signalling, its over-production may cause neuronal energy compromise leading to neurodegeneration.

Ischemia-elicited Oxidative Modulation of Ca2+/Calmodulin-dependent Protein Kinase II

“…Superoxide is generated by xanthine oxidase, NADPH oxidases, and release from the mitochondrial respiratory chain. Under pathophysiological conditions, such as ischemia or seizure, a large quantity of NO is generated by over-activation of NMDA receptors or by inducible NO synthase from neighboring glia (25). Cerebral ischemia also causes mitochondrial dysfunction, which increases the production of superoxide.…”

“…The purified enzyme was kept frozen at Ϫ20°C, and purity was checked by SDS-PAGE. CaMKII activity was measured at 30°C for 2 min in a mixture (25 Treatment of Purified CaMKII with Oxidants-CaMKII (1 mg/ml, 50 -100 l) was incubated in 10 mM potassium phosphate buffer, pH 7.5, containing 10% glycerol, and 2 mM DTT at room temperature for 30 min to reduce protein sulfhydryl groups. These proteins were then loaded on G-25 MicroSpin columns, which had been equilibrated with the same buffer, and centrifuged at 5000 rpm for 7 s in an Eppendorf Micro centrifuge to separate reduced kinase from DTT.…”

“…Especially during ischemic and excitotoxic stress, a sustained elevation of intracellular Ca 2ϩ and energy depletion causes uncoupling of mitochondrial oxidative phosphorylation that generates a high level of these reactive oxygen species from neurons as well as from glia cells (25,26). It is conceivable that these reactive oxygen species could modulate CaMKII activity by direct oxidation of this protein, which constitutes 1-2% of total brain protein (27), as well as by oxidation of its activator, CaM (28).…”

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

“…Because of the discrete pre-and postsynaptic, and intraand extrasynaptic, localization of the various receptor subunits (Bernard and Bolam, 1998;Wang and Pickel, 2000;Dunah and Standaert, 2003;Galvan et al, 2006), striatal NMDA receptor stimulation has multiple and complex functional effects. Moderate activation of NMDA receptors controls, for example, monoaminergic, cholinergic, glutamatergic and peptidergic neurotransmission (Becquet et al, 1990;Young and Bradford, 1993;Knauber et al, 1999;Hathway et al, 2001;Radke et al, 2001;Marti et al, 2005) and, as a consequence, affects synaptic plasticity (Centonze et al, 2004;Dang et al, 2006), motor function (Hallett et al, 2005;Gardoni et al, 2006) and cellular bioenergetics (Moncada and Bolanos, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.…”

Efeitos neurodegenerativos da metilecgonidina e da cocaína em cultura celular primária de hipocampo

“…Uma delas é mediada pela ação exacerbada do glutamato, um neurotransmissor excitatório do SNC que, em condições fisiológicas, está envolvido na plasticidade neuronal, na memória, no aprendizado e no comportamento (ALBRIGHT et al, 2000). A ativação excessiva de receptores NMDA causada pelo excesso de glutamato, fenômeno conhecido como excitotoxicidade (WODJA et al, 2008), promove um aumento de Ca 2+ citosólico que ativa enzimas dependentes de Ca 2+ , como a NOS, aumentando a formação de EROS que, finalmente, pode culminar com a peroxidação lipídica e a morte neuronal (KOO et al, 2006;MONCADA et al, 2006). A produção de EROS pode ocorrer também por intermédio de processos neuroinflamatórios decorrentes de fatores de risco como alterações genéticas, traumas na região craniana, isquemias agudas e a exposição aos poluentes ambientais (FLOYD, 1999).…”