Regulation of adenosine levels during cerebral ischemia

Abstract

Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury. Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes. Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism. Recent studies have used genetically modified mice to investigate the relative contributions of intra-and extracellular pathways for adenosine formation. The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase. From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions.

Paeoniflorin ameliorates ischemic neuronal damage in vitro via adenosine A1 receptor-mediated transactivation of epidermal growth factor receptor

“…When ischemic injury occurs, extracellular adenosine increases and activates A 1 R, which works as a neuromodulator to inhibit excitotoxic neuronal injury [11] . This induces presynaptic A 1 Rs to decrease the release of glutamate and relieves Ca 2+ overloading at postsynaptic A 1 Rs [12] .…”

Activity of the astrocytes' adenosine signaling system components in model of traumatic brain injury in vivo and in vitro

“…Dr Parkison i saradnici su tokom poslednjih godina pokazali da u hipoksičnim uslovima u kulturi neuroni otpuštaju Ado, dok astrociti doprinose formiranju Ado putem e-5NT [81]. S a druge strane, in vitro studije iste grupe rađene na presecima hipokampusa u kulturi su pokazale da neuronski transporter ENT1 posreduje preuzimanju vanćelijskog Ado u hipoksiji/ishemiji [53,[82][83][84]. Neslaganja u rezultatima dobijenim u različitim eksperimentalnim postavkama ostavljaju otvorenim pitanje koji tip moždanih ćelija i u kojoj meri doprinosi kruženju adenozina nakon povrede.…”

“…preuzimali Ado iz vanćelijske sredine [82]. S obzirom na značajnu eskpresiju ENT1 i ENT2 na astrocitima, ostaje nepoznato kakva je uloga ovih transportera u putu adenozina posredovanom astrocitima.…”

“…Ovo je posebno važno u patološkim uslovima, gde Ado iskazuje neuroprotektivno dejstvo [17,82,252,253]. S obzirom na to da Ado reguliše neuronsku aktivnost u fiziološkim i patološkim stanjima, mehanizam kontrole mora da omogući brze promene vanćelijskih koncetracija Ado [31,254].…”

“…Ipak, daleko manji broj studija se odnosi na ćelijsko poreklo Ado u mozgu; tu postoje različita mišljenja o poreklu Ado u vanćelijskom prostoru, koje se pripisuje ili enzimima ili transporterima [82].…”