Blood purine measurements as a rapid real-time indicator of reversible brain ischaemia

Abstract

To preserve the disequilibrium between ATP and ADP necessary to drive cellular metabolism, enzymatic pathways rapidly convert ADP to adenosine and the downstream purines inosine and hypoxanthine. During ischaemia, these same pathways result in the production of purines. We performed a prospective observational study to test whether purine levels in arterial blood might correlate with brain ischaemia. We made real-time perioperative measurements, via microelectrode biosensors, of the purine levels in untreated arterial blood from 18 patients undergoing regional anaesthetic carotid endarterectomy. Pre-operatively, the median purine level was 2.4 μM (95% CI 1.3–4.0 μM); during the cross-clamp phase, the purines rose to 6.7 μM (95% CI 4.7–11.5 μM) and fell back to 1.9 μM (95% CI 1.4–2.7 μM) in recovery. Three patients became unconscious during carotid clamping, necessitating insertion of a temporary carotid shunt to restore cerebral blood flow. In these, the pre-operative median purine level was 5.4 μM (range 4.7–6.1 μM), on clamping, 9.6 μM (range 9.4–16.1 μM); during shunting, purines fell to below the pre-operative level (1.4 μM, range 0.4–2.9 μM) and in recovery 1.8 μM (range 1.8–2.6 μM). Our results suggest that blood purines may be a sensitive real-time and rapidly produced indicator of brain ischaemia, even when there is no accompanying neurological obtundation.

A scoping review of pre-hospital technology to assist ambulance personnel with patient diagnosis or stratification during the emergency assessment of suspected stroke

“…The role of additional biomarkers may be crucial. There is evidence supporting the measurement of purines as an indicator of cerebral ischaemia, where increases corresponded with hypo-perfusion induced by carotid clamping [53] and correlated with greater stroke volumes in the emergency department [42,54]. However, the applicability of this to the pre-hospital setting is currently unconfirmed.…”

The combination of ribose and adenine promotes adenosine release and attenuates the intensity and frequency of epileptiform activity in hippocampal slices: Evidence for the rapid depletion of cellular ATP during electrographic seizures

“…; Frenguelli ; Tian et al . ). This loss of salvageable substrates, together with injury‐induced mitochondrial dysfunction, and indeed potential ATP consumption by mitochondria, likely explains the profound and protracted depletion of cerebral ATP after various forms of injury (Frenguelli ).…”

“…Under normal circumstances this constraint is met, and substrates are available in sufficient quantities to meet the demand for ATP. However, under conditions of ATP depletion, most notably cerebral ischaemia, ATP is metabolized to compounds that are lost to the circulation, or, in the case of xanthine, beyond salvage (Weigand et al 1999;Frenguelli 2017;Tian et al 2017). This loss of salvageable substrates, together with injury-induced mitochondrial dysfunction, and indeed potential ATP consumption by mitochondria, likely explains the profound and protracted depletion of cerebral ATP after various forms of injury (Frenguelli 2017).…”

“…; Tian et al . ). One such metabolite is hypoxanthine, which is utilized by one branch of the purine salvage pathway (Ipata et al .…”

“…Such insults cost the brain dearly in terms of repeated demands on the energy currency. This situation is exacerbated by the loss from the brain into the bloodstream of adenosine and subsequent metabolites (Weigand et al 1999;Tian et al 2017). One such metabolite is hypoxanthine, which is utilized by one branch of the purine salvage pathway (Ipata et al 2011), the primary route by which adenine nucleotides are synthesized in the brain (Fig.…”