Further investigations were concerned to study the mechanism

Further investigations were concerned to study the mechanisms by which GABA modulates adenosine-mediated effects in hippocampal tissue. From these results it can be concluded that endogenous GABA exerts an inhibitory effect through GABAA receptors via a predominant adenosine-mediated action and this is an A1R-mediated ability to inhibit synaptic transmission [29]. It is well documented that activation of GABAA receptors is effective in limiting neuronal ischemic damage [53] and endogenous adenosine that arises during hypoxia acts neuroprotectively partly by activating A1Rs [39]. Therefore, the contribution and potential interactions of GABA and adenosine as modulators of synaptic transmission during hypoxia has been investigated. Activation of A1Rs inhibits the release of GABA from the ischemic Merimepodib in vivo [61]. In contrast, the administration of an A1R agonist in the hippocampus failed to affect the release of GABA during ischemia [40]. In the light of these controversial results, the role of the two neuromodulators was investigated in the CA1 area of rat hippocampal slices during hypoxia using selective A1R antagonists [52]. Indeed, activation of A1R and GABAA receptors is partly involved in the inhibition of synaptic transmission during hypoxia. The action of GABA becomes evident when A1Rs are blocked. Regarding the desensitization of A1Rs during hypoxia [73,86], it may be assumed that GABAA-mediated inhibition of the synaptic transmission is evident when the A1R is desensitized or down regulated [52]. Co-modulation by A1Rs and GABAA receptors was also suggested in acute cerebellar ethanol-induced ataxia. Using GABAA and A1R agonists and antagonists, respectively, a functional similarity between GABAA receptors and A1Rs has been shown even through both receptor types are known to couple to different signaling systems [18]. This provides conclusive evidence that A1Rs and GABAA receptors both play a co-modulatory role in ethanol-induced cerebellar ataxia without any direct interaction.
Concluding remarks The key receptor in regulation the neuronal transmission may be the A2AR, whereas the interaction of the A1R with metabotropic and ionotropic receptors serves as fine-tuning to inhibit synaptic transmission. However, they play an important protective role during pathophysiological conditions. The activation initiates a fast inhibition of the glutamatergic neurotransmission and the receptor interactions may contribute to its maintenance or can support the A1R mediated effects.
Conflict of interest
Introduction Inflammatory response is the result of a complex interaction between immune cells and several soluble factors, aimed at protecting the host from invasion by microorganisms and eliminate debris at sites of tissue injury in order to maintain tissue homeostasis [1,2]. However, an exuberant immune/inflammatory response, not adequately balanced by endogenous mechanisms of homeostatic control, can lead to persistent and abnormal forms of collateral tissue damage [1,2]. In this regard, adenosine, a purine nucleoside that accumulates in the extracellular space at sites of tissue damaged is a pivotal player in the modulation of immune responses and in restraining inflammatory tissue damage [1]. Indeed, over the years, a number of studies have identified extracellular adenosine as a ‘retaliatory metabolite’, which indicates that it is generated as a result of cellular injury or stress, and that through interacting with specific G protein-coupled receptors, it regulates the immune/inflammatory cell functions[[3], [4], [5]] to protect tissues from injury and stress [[5], [6], [7], [8], [9], [10], [11]]. However, chronic exposure to adenosine may under some conditions may be harmful, as adenosine can create an immunosuppressed niche, which is necessary for the onset and development of neoplasia and infection [[12], [13], [14], [15], [16]] [17].