Metabolic Challenge to Glia Activates an Adenosine-Mediated Safety Mechanism that Promotes Neuronal Survival by Delaying the Onset of Spreading Depression Waves

Abstract

In a model of glial-specific chemical anoxia, we have examined how astrocytes influence both synaptic transmission and the viability of hippocampal pyramidal neurons. This relationship was assessed using electrophysiological, pharmacological, and biochemical techniques in rat slices and cell cultures, and oxidative metabolism was selectively impaired in glial cells by exposure to the mitochondrial gliotoxin, fluoroacetate. We found that synaptic transmission was blocked shortly after inducing glial metabolic stress and peri-infarct-like spreading depression (SD) waves developed within 1 to 2 h of treatment. Neuronal electrogenesis was not affected until SD waves developed, thereafter decaying irreversibly. The blockage of synaptic transmission was totally reversed by A 1 adenosine receptor antagonists, unlike the development of SD waves, which appeared earlier under these conditions. Such blockage led to a marked reduction in the electrical viability of pyramidal neurons 1 h after gliotoxin treatment. Cell culture experiments confirmed that astrocytes indeed release adenosine. We interpret this early glial response as a novel safety mechanism that allocates metabolic resources to vital processes when the glia itself sense an energy shortage, thereby delaying or preventing entry into massive lethal ischemic-like depolarization. The implication of these results on the functional recovery of the penumbra regions after ischemic insults is discussed.

Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

“…40,41 We instead suggest that the bulk of adenosine released in stroke is pulsatile and linked to occurrence of SDs and not to gradual deterioration of metabolic status. If this is true, it follows that the more adenosine accumulation is observed, the more SDs (or the worse the SDs) may be inferred to be occurring.…”

“…Otherwise, adenosine transients were not seen before SD, in intervals between SDs, or in animals without SDs (P o 0.001, maximum peak-to-trough adenosine amplitude from dMCAO animals without SD compared with signals recorded in animals immediately after SD). Isoelectricity was observed at the onset of recording in 3 of 14 dMCAO animals, and could indicate these recordings were made from the belt of normally perfused yet electrocorticographically depressed tissue surrounding ischemic lesions, 40 or that an undetected spreading depression or nonspreading depression (possibly mediated by adenosine 41 ) may have occurred before recording.…”

Role of The Purinergic Neuromodulation System in Epilepsy

“…For instance the cardioprotective effect of adenosine is related to the ability of A 1 R activation to control glucose and glycogen metabolism [168][169][170][171]. Adenosine also affects both brain neuronal and astrocytic intermediary metabolism [63,[172][173][174][175][176]. In particular, A 1 R can affect AMPK [177], p38 MAPK [178][179][180][181] or preserve mitochondria function through control of K ATP channels [182][183][184][185][186]; these are all pathways known to coordinate primary metabolism and to have a profound impact on neuronal function and viability [187][188][189].…”

“…This paves the way to consider this A 1 R-mediated preconditioning as a likely candidate mechanism to understand the 'anti-epileptic' potential of A 1 R. An hypothetic scenario can be advanced, based on a coordinated action between different adenosine receptors and between neurons and astrocytes (see Fig. 5): thus, the initiation of seizure activity increases the extracellular levels of adenosine [138,139]; this adenosine can activate astrocytic adenosine receptors further increasing adenosine release through ATP-mediated spreading depression [174,208,209] and through increases of interleukin-6 mRNA expression and release [210,211]; spreading of this activation 'wave' through the astrocytic syncytium would allow a simultaneous increase of adenosine as well as a bolstering of A 1 R expression and density, promoted by interleukin-6 [212,213] in neurons adjacent to the seizure foci. Overall, this should contribute to limit seizure spreading, through synaptic A 1 R and to allow neighbouring neurons to better cope with seizures through metabolic down-regulation.…”

Cortical Spreading Depression Shifts Cell Fate Determination of Progenitor Cells in the Adult Cortex

“…It was reported that dysfunction of astrocytes in the brain led to epileptiform activity and occasionally to convulsive seizures (Willoughby et al, 2003;Lian and Stringer, 2004b). Moreover, it has been also suggested that inhibition of metabolism in astrocytes increases neuronal vulnerability to SD (Lian and Stringer, 2004c;Canals et al, 2008). Although astrocytes are thought to play a crucial role in the maintenance of neuronal activity as well as relieving neuronal damage during intense neuronal excitation, involving SD and seizures, the regulatory system for supplying astrocytes by neural activity remains unknown.…”