Role Of Adenosine A1 Receptors Research Articles

Role of Adenosine A1 Receptor in Sleep Deprivation-Induced Neuroinflammation: Insights on Rapid Eye Movement Sleep and Fear Extinction Memory Recall in Rats

Role of Adenosine A1 Receptor in Sleep Deprivation-Induced Neuroinflammation: Insights on Rapid Eye Movement Sleep and Fear Extinction Memory Recall in Rats

Putative Role of Adenosine A1 Receptors in Exogenous Ketone Supplements-Evoked Anti-Epileptic Effect.

Approximately 30% of patients with epilepsy are drug-refractory. There is an urgent need to elucidate the exact pathophysiology of different types of epilepsies and the mechanisms of action of both antiseizure medication and metabolic therapies to treat patients more effectively and safely. For example, it has been demonstrated that exogenous ketone supplement (EKS)-generated therapeutic ketosis, as a metabolic therapy, may decrease epileptic activity in both animal models and humans, but its exact mechanism of action is unknown. However, it was demonstrated that therapeutic ketosis, among others, can increase adenosine level, which may enhance activity of A1 adenosine receptors (A1Rs) in the brain. It has also been demonstrated previously that adenosine has anti-epileptic effect through A1Rs in different models of epilepsies. Thus, it is possible that (i) therapeutic ketosis generated by the administration of EKSs may exert its anti-epileptic effect through, among other mechanisms, increased adenosine level and A1R activity and that (ii) the enhanced activity of A1Rs may be a necessary anti-epileptic mechanism evoked by EKS administration-generated ketosis. Moreover, EKSs can evoke and maintain ketosis without severe side effects. These results also suggest that the therapeutic application of EKS-generated ketosis may be a promising opportunity to treat different types of epilepsies. In this literature review, we specifically focus on the putative role of A1Rs in the anti-epileptic effect of EKS-induced ketosis.

Neuroprotection by trans-resveratrol in rats with N-methyl-D-aspartate (NMDA)–induced retinal injury: Insights into the role of adenosine A1 receptors

Adenosine A1 receptors (AA1R) have been shown to counteract N-methyl-D-aspartate (NMDA)–mediated glutamatergic excitotoxicity. In the present study, we investigated the role of AA1R in neuroprotection by trans-resveratrol (TR) against NMDA-induced retinal injury. In total, 48 rats were divided into the following four groups: normal rats pretreated with vehicle; rats that received NMDA (NMDA group); rats that received NMDA after pretreatment with TR; and rats that received NMDA after pretreatment with TR and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an AA1R antagonist. Assessment of general and visual behaviour was performed using the open field test and two-chamber mirror test, respectively, on Days 5 and 6 post NMDA injection. Seven days after NMDA injection, animals were euthanized, and eyeballs and optic nerves were harvested for histological parameters, whereas retinae were isolated to determine the redox status and expression of pro- and anti-apoptotic proteins. In the present study, the retinal and optic nerve morphology in the TR group was protected from NMDA-induced excitotoxic damage. These effects were correlated with the lower retinal expression of proapoptotic markers, lipid peroxidation, and markers of nitrosative/oxidative stress. The general and visual behavioural parameters in the TR group showed less anxiety-related behaviour and better visual function than those in the NMDA group. All the findings observed in the TR group were abolished by administration of DPCPX.

The role of adenosine A1 receptor in the analgesia induced by myofascial reorganization technique in mice with peripheral inflammation

The role of adenosine A1 receptor in the analgesia induced by myofascial reorganization technique in mice with peripheral inflammation

The role of adenosine A1 receptor on immune cells.

Adenosine, acting as a regulator by mediating the activation of G protein-coupled adenosine receptor families (A1, A2A, A2B, and A3), plays an important role under physiological and pathological conditions. As the receptor with the highest affinity for adenosine, the role of adenosine A1 receptor (A1R)-mediated adenosine signaling pathway in the central nervous system has been well addressed. However, functions of A1R on immune cells are less summarized. Considering that some immune cells express multiple types of adenosine receptors with distinct effects and varied density, exogenous adenosine of different concentrations may induce divergent immune cell functions. The literatures about the expression of A1R and its regulation on immune cells and how it regulates the function of immune cells were searched on PubMed and Google Scholar. In this review, we discussed the effects of A1R on immune cells, including monocytes, macrophages, neutrophils, dendritic cells, and microglia, and focused on the role of A1R in regulating immune cells in diseases, which may facilitate our understanding of the mechanisms by which adenosine affects immune cells through A1R.

Role of A1 adenosine receptor in survival of human lung cancer

Adenosine, as a purine nucleoside, has a crucial role in the tumorigenesis through interaction with adenosine receptors subtypes A1, A2a, A2b, and A3. The role of A1 adenosine receptor (A1AR) in lung cancer has not yet been determined. Here we assessed the role of A1AR in lung cancer. Our results demonstrated a significant increase in A1AR in lung tumors tissue relative to adjacent tumor margins. Our data also indicated A1AR antagonist inhibited cell growth and induced cell apoptosis in A549 lung cancer cells. Treatment of lung cancer cells with A1AR antagonist also increased caspase 3 and 7 activity in these cells. In summary, this study showed that A1AR highly expressed in lung tumor relative to tumor margins, and A1AR has a crucial role in survival of lung cancer.

Neuroprotection by Trans-Resveratrol in Rats With Intracerebral Hemorrhage: Insights into the Role of Adenosine A1 Receptors.

Given the neuroprotective effects of trans-resveratrol (RV), this study aimed to investigate the involvement of the adenosine A1 receptor (A1R) in RV-mediated neuroprotection in a rat intracerebral hemorrhage (ICH) model induced by intrastriatal injection of collagenase. Rats were divided into 5 groups: (1) control, (2) sham-operated, (3) ICH pretreated with vehicle, (4) ICH pretreated with RV, and (5) ICH pretreated with RV and the A1R antagonist DPCPX. At 48 hours after ICH, the rats were subjected to neurological testing. Brain tissues were assessed for neuronal density and morphological features using routine and immunohistochemical staining. Expression of tumor necrosis factor-α (TNF-α), caspase-3, and RIPK3 proteins was examined using ELISA. A1R, MAPK P38, Hsp90, TrkB, and BDNF genes were examined using RT-qPCR. RV protected against neurological deficits and neuronal depletion, restored the expression of TNF-α, CASP3, RIPK3, A1R, and Hsp90, and increased BDNF/TrkB. DPCPX abolished the effects of RV on neurological outcomes, neuronal density, CASP3, RIPK3, A1R, Hsp90, and BDNF. These data indicate that the neuroprotection by RV involves A1R and inhibits CASP3-dependent apoptosis and RIPK3-dependent necroptosis in the perihematoma region; this is likely to be mediated by crosstalk between A1R and the BDNF/TrkB pathway.

The role of adenosine A1 receptor in the peripheral tramadol's effect in the temporomandibular joint of rats

Peripheral tramadol's delivery in the temporomandibular joint (TMJ) leads to significant analgesic outcomes and inflammatory process's resolvent actions. Mechanistically, these properties are apart from the opioid system. Nevertheless, the molecular mechanisms behind these effects are still unclear. Therefore, the present study investigated the hypothesis that adenosine A1 receptors are involved in the tramadol-induced analgesic and anti-inflammatory effects in the TMJ. Animals were pretreated with an intra-TMJ injection of DPCPX (antagonist of A1 receptor) or tramadol and subsequent nociceptive challenge with an intra-TMJ injection of 1.5% formalin. For over 45 min, the nociceptive behavior was quantitated, and by the end of this assessment, the animals were euthanized, and the periarticular tissue was collected. Lastly, an in vitro assay of BMDM (Bone Marrow-Derived Macrophages) was performed to investigate tramadol activity in macrophages. The intra-TMJ injection of tramadol ameliorates formalin-induced hypernociception along with inhibiting leukocyte migration. The tramadol's peripheral anti-inflammatory effect was mediated by the adenosine A1 receptor and was associated with increased protein expression of α2a-adrenoceptor in the periarticular tissues (p < 0.05: ANOVA, Tukey’s test). Also, tramadol inhibits formalin-induced leukocyte migration and protein expression of P2X7 receptors in the periarticular tissue (p < 0.05); however, DPCPX did not alter this effect (p > 0.05). Moreover, DPCPX significantly reduced the protein expression of the M2 macrophage marker, MRC1. In BMDM, tramadol significantly reduces inflammatory cytokines release, and DPCPX abrogated this effect (p < 0.05). We identify tramadol's peripheral effect is mediated by adenosine A1 receptor, possibly expressed in macrophages in the TMJ tissue. We also determined an important discovery related to the activation of A1R/α2a receptors in the tramadol action.

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field’s understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.

Blockade of adenosine A1 receptor in nucleus tractus solitarius attenuates baroreflex sensitivity response to dexmedetomidine in rats

The α2-adrenergic receptor (α2-AR) agonist dexmedetomidine increases baroreflex sensitivity (BRS). In the current study, we examined the potential role of adenosine A1 receptor (A1R) within the nucleus tractus solitaries (NTS) in such a response. Briefly, adult male Sprague-Dawley rats were anesthetized and randomly received microinjection of selective A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 pmol/1 μl) or saline vehicle into the right NTS. Ten min after the microinjection, dexmedetomidine infusion started at a rate of 30 μg/kg over 15 min followed by infusion at 15 μg·kg−1·h−1 for 105 min, or 100 μg/kg over 15 min followed by infusion at 50 μg·kg−1·h−1 for 105 min. BRS was examined using a standard phenylephrine method prior to infusion (T0), 60 min (T1) and 120 min (T2) after dexmedetomidine infusion started. Adenosine concentration in plasma and brainstem was measured with high-performance liquid chromatography with vs. without α2-AR antagonist atipamezole pretreatment (0.5 mg/kg, i.p.). Dexmedetomidine increased BRS at both 30 (T0: 0.55 ± 0.25 vs. T1: 2.45 ± 0.37, T2: 2.26 ± 0.56 ms/mmHg, P < 0.05) and 100 μg/kg (T0: 0.63 ± 0.24 vs. T1: 6.21 ± 1.87, T2: 6.30 ± 2.12 ms/mmHg, P < 0.05). DPCPX pretreatment obliterated BRS response to 100-μg/kg dexmedetomidine. At 100 μg/kg, dexmedetomidine increased adenosine concentration in plasma (0.23 ± 0.11 to 0.45 ± 0.07 μg/ml, P < 0.05) and brainstem (1.46 ± 0.30 to 2.52 ± 0.22 μg/ml, P < 0.05); such effect was blocked by atipamezole pretreatment. Western blot analysis showed α2-AR up-regulation by 100-μg/kg dexmedetomidine, which can be prevented by DPCPX. Double-labeling with glial fibrillary acidic protein showed α2-AR up-regulation in astrocytes in the NTS. These results suggest that dexmedetomidine enhances baroreflex sensitivity, possibly by increasing adenosine in NTS and α2-AR expression in astrocytes.

The role of adenosine A1 receptors in the nucleus accumbens during morphine withdrawal.

Opioids are effective analgaesic agents, but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is not life-threatening. Studies have shown that the mesocorticolimbic system, especially the nucleus accumbens, is an important region in drug addiction and adenosinereceptors play a modulatory role in the mechanism of action of drug dependence and withdrawal. The aim of this study was to investigate the effects of the selective A1 receptor agonist CPA (N6 -cyclopentyladenosine) on withdrawal symptoms, and the concentration of dopamine and noradrenaline in the nucleus accumbens and locomotor activity behaviour during naloxone-precipitated withdrawal in morphine-dependent rats. The local administration of CPA (1.5, 3.0, and 6.0mmol/L bilateral 250nL) into the nucleus accumbens decreased the Gellert-Holtzman withdrawal scale, and increased concentrations of dopamine and noradrenaline in the same region during naloxone-induced withdrawal. Our findings suggest that administration of the A1 receptor agonist significantly decreased withdrawal behaviours and increased dopamine and noradrenaline concentrations in opioid withdrawal in a dose-dependent manner. These results demonstrate that adenosine receptors should be examined as a potential mechanism that could be exploited for the treatment of morphine withdrawal.

Low-frequency Stimulation Decreases Hyperexcitability Through Adenosine A1 Receptors in the Hippocampus of Kindled Rats.

Introduction:In this study, the role of A1 adenosine receptors in improving the effect of Low-Frequency Electrical Stimulation (LFS) on seizure-induced hyperexcitability of hippocampal CA1 pyramidal neurons was investigated.Methods:A semi-rapid hippocampal kindling model was used to induce seizures in male Wistar rats. Examination of the electrophysiological properties of CA1 pyramidal neurons of the hippocampus using whole-cell patch-clamp recording 48 h after the last kindling stimulation revealed that the application of LFS as two packages of stimulations at a time interval of 6 h for two consecutive days could significantly restore the excitability CA1 pyramidal neurons evidenced by a decreased in the of the number of evoked action potentials and enhancement of amplitude, maximum rise slope and decay slope of the first evoked action potential, rheobase, utilization time, adaptation index, first-spike latency, and post-AHP amplitude. Selective locked of A1 receptors by the administration of 8-Cyclopentyl-1,3-dimethylxanthine (1 μM, 1 μl, i.c.v.) before applying each LFS package, significantly reduced LFS effectiveness in recovering these parameters.Results:On the other hand, selective activation of A1 receptors by an injection of N6-cyclohexyladenosine (10 μM, 1 μl, i.c.v.), instead of LFS application, could imitate LFS function in improving these parameters.Conclusion:It is suggested that LFS exerts its efficacy on reducing the neuronal excitability, partially by activating the adenosine system and activating its A1 receptors.

Mild hypothermia protects synaptic transmission from experimental ischemia through reduction in the function of nucleoside transporters in the mouse hippocampus

Ischemia, a severe metabolic stress, increases adenosine levels and causes the suppression of synaptic transmission through adenosine A1 receptors. Although temperature also regulates extracellular adenosine levels, the effect of temperature on ischemia-induced activation of adenosine receptors is not yet fully understood. Here we examined the role of adenosine A1 receptors in mild hypothermia-mediated neuroprotection during the acute phase of ischemia. Severe ischemia-induced neurosynaptic impairment was reproduced by oxygen-glucose deprivation at normothermia (36 °C) and assessed with extracellular recordings or whole-cell patch clamp recordings in acute hippocampal slices in mice. Mild hypothermia (32 °C) induced the protection of synaptic transmission by activating adenosine A1 receptors. Stricter hypothermia (28 °C) caused additional neuroprotective effects by extending the onset time to anoxic depolarization; however, this effect was not associated with adenosine A1 receptors. The response of exogenous adenosine-induced inhibition of hippocampal synaptic transmission was increased by lowering the temperature to 32 °C or 28 °C. Hypothermia also reduced the function of dipryidamole-sensitive nucleoside transporters. These findings suggest that an increased response of adenosine A1 receptors, caused by a reduction in the function of nucleoside transporters, is one mechanism by which therapeutic hypothermia (usually used within the mild range) mediates neurosynaptic protection in the acute phase of stroke.

Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors

Trait-like differences in cognitive performance after sleep loss put some individuals more at risk than others, the basis of such disparities remaining largely unknown. Similarly, interindividual differences in impairment in response to alcohol intake have been observed. We tested whether performance impairments due to either acute or chronic sleep loss can be predicted by an individual's vulnerability to acute alcohol intake. Also, we used positron emission tomography (PET) to test whether acute alcohol infusion results in an up-regulation of cerebral A1 adenosine receptors (A1ARs), similar to the changes previously observed following sleep deprivation. Sustained attention in the psychomotor vigilance task (PVT) was tested in 49 healthy volunteers (26 ± 5 SD years; 15 females) (i) under baseline conditions: (ii) after ethanol intake, and after either (iii) total sleep deprivation (TSD; 35 hours awake; n = 35) or (iv) partial sleep deprivation (PSD; four nights with 5 hours scheduled sleep; n = 14). Ethanol- versus placebo-induced changes in cerebral A1AR availability were measured in 10 healthy male volunteers (31 ± 9 years) with [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX) PET. Highly significant correlations between the performance impairments induced by ethanol and sleep deprivation were found for various PVT parameters, including mean speed (TSD, r = 0.62; PSD, r = 0.84). A1AR availability increased up to 26% in several brain regions with ethanol infusion. Our studies revealed individual trait characteristics for being either vulnerable or resilient to both alcohol and to sleep deprivation. Both interventions induce gradual increases in cerebral A1AR availability, pointing to a potential common molecular response mechanism.

Role of Adenosine A1 Receptors in Remote Ischemic Preconditioning Protection

Role of Adenosine A1 Receptors in Remote Ischemic Preconditioning Protection

Role of Adenosine A1 Receptors in Remote Ischemic Preconditioning Protection

Background: Adenosine is involved in classical preconditioning acting especially through adenosine A1 and A3 receptors. Objective: The objective of our study was to evaluate whether remote ischemic preconditioning (rIPC) activates adenosine A1 receptors before ischemia or at the onset of reperfusion to reduce myocardial infarct size. Methods: Isolated rat hearts were subjected to 30-min ischemia and 60-min reperfusion (I/R). In a second group, a rIPC protocol (3 cycles of hindlimb ischemia/reperfusion) was performed. Infarct size was measured with triphenyltetrazolium staining. Results: Remote IPC significantly decreased infarct size. This effect was abolished when DPCPX (A1 receptor blocker) or L-NAME (nitric oxide synthesis inhibitor) were administered during reperfusion. Conclusions: We demonstrated in the isolated rat heart that rIPC reduces myocardial infarction by activation of the adenosine A1 receptor at the onset of the reperfusion period. This protective effect would be also mediated by the activation of nitric oxide synthase during reperfusion.

Caffeine Controls Glutamatergic Synaptic Transmission and Pyramidal Neuron Excitability in Human Neocortex.

Caffeine is the most widely used psychoactive drug, bolstering attention and normalizing mood and cognition, all functions involving cerebral cortical circuits. Whereas studies in rodents showed that caffeine acts through the antagonism of inhibitory A1 adenosine receptors (A1R), neither the role of A1R nor the impact of caffeine on human cortical neurons is known. We here provide the first characterization of the impact of realistic concentrations of caffeine experienced by moderate coffee drinkers (50 μM) on excitability of pyramidal neurons and excitatory synaptic transmission in the human temporal cortex. Moderate concentrations of caffeine disinhibited several of the inhibitory A1R-mediated effects of adenosine, similar to previous observations in the rodent brain. Thus, caffeine restored the adenosine-induced decrease of both intrinsic membrane excitability and excitatory synaptic transmission in the human pyramidal neurons through antagonism of post-synaptic A1R. Indeed, the A1R-mediated effects of endogenous adenosine were more efficient to inhibit synaptic transmission than neuronal excitability. This was associated with a distinct affinity of caffeine for synaptic versus extra-synaptic human cortical A1R, probably resulting from a different molecular organization of A1R in human cortical synapses. These findings constitute the first neurophysiological description of the impact of caffeine on pyramidal neuron excitability and excitatory synaptic transmission in the human temporal cortex, providing adequate ground for the effects of caffeine on cognition in humans.

Tremorolytic effect of 5'-chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the harmaline-induced model in rats.

The aim of this study was to examine the role of adenosine A1 receptors in the harmaline-induced tremor in rats using 5'-chloro-5'-deoxy-(±)-ENBA (5'Cl5'd-(±)-ENBA), a brain-penetrant, potent, and selective adenosine A1 receptor agonist. Harmaline was injected at a dose of 15mg/kg ip and tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15Hz (AP2) and by tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. 5'Cl5'd-(±)-ENBA (0.05-0.5mg/kg ip) dose dependently reduced the harmaline-induced tremor and this effect was reversed by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of adenosine A1 receptors (1mg/kg ip). Harmaline increased the zif-268 mRNA expression in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei, and motor cortex. 5'Cl5'd-(±)-ENBA reversed these increases in all the above structures. DPCPX reduced the effect of 5'Cl5'd-(±)-ENBA on zif-268 mRNA in the motor cortex. This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential tremor.

Biochemical and Pharmacological Role of A1 Adenosine Receptors and Their Modulation as Novel Therapeutic Strategy.

Adenosine, the purine nucleoside, mediates its effects through activation of four G-protein coupled adenosine receptors (ARs) named as A1, A2A, A2B and A3. In particular, A1ARs are distributed through the body, primarily inhibitory in the regulation of adenylyl cyclase activity and able to reduce the cyclic AMP levels. Considerable advances have been made in the pharmacological and molecular characterization of A1ARs, which had been proposed as targets for the discovery and drug design of antagonists, agonists and allosteric enhancers. Several lines of evidence indicate that adenosine interacting with A1ARs may be an endogenous protective agent in the human body since it prevents the damage caused by various pathological conditions, such as in ischemia/hypoxia, epileptic seizures, excitotoxic neuronal injury and cardiac arrhythmias in cardiovascular system. It has also been reported that one of the most promising targets for the development of new anxiolytic drugs could be A1ARs, and that their activation may reduce pain signaling in the spinal cord. A1AR antagonists induce diuresis and natriuresis in various experimental models, mediating the inhibition of A1ARs in the proximal tubule which is primarily responsible for reabsorption and fluid uptake. In addition, the results of various studies indicate that adenosine is present within pancreatic islets and is implicated through A1ARs in the regulation of insulin secretion and in glucose concentrations. In the present paper it will become apparent that A1ARs could be implicated in the pharmacological treatment of several pathologies with an important influence on human health.

A1 adenosine receptor attenuates intracerebral hemorrhage-induced secondary brain injury in rats by activating the P38-MAPKAP2-Hsp27 pathway.

BackgroundThis study was designed to determine the role of the A1 adenosine receptors in intracerebral hemorrhage (ICH)-induced secondary brain injury and the underlying mechanisms.MethodsA collagenase-induced ICH model was established in Sprague–Dawley rats, and cultured primary rat cortical neurons were exposed to oxyhemoglobin at a concentration of 10 μM to mimic ICH in vitro. The A1 adenosine receptor agonist N(6)-cyclohexyladenosine and antagonist 8-phenyl-1,3-dipropylxanthine were used to study the role of A1 adenosine receptor in ICH-induced secondary brain injury, and antagonists of P38 and Hsp27 were used to study the underlying mechanisms of A1 adenosine receptor actions.ResultsThe protein level of A1 adenosine receptor was significantly increased by ICH, while there was no significant change in protein levels of the other 3 adenosine receptors. In addition, the A1 adenosine receptor expression could be increased by N(6)-cyclohexyladenosine and decreased by 8-phenyl-1,3-dipropylxanthine under ICH conditions. Activation of the A1 adenosine receptor attenuated neuronal apoptosis in the subcortex, which was associated with increased phosphorylation of P38, MAPK, MAPKAP2, and Hsp27. Inhibition of the A1 adenosine receptor resulted in opposite effects. Finally, the neuroprotective effect of the A1 adenosine receptor agonist N(6)-cyclohexyladenosine was inhibited by antagonists of P38 and Hsp27.ConclusionsThis study demonstrates that activation of the A1 adenosine receptor by N(6)-cyclohexyladenosine could prevent ICH-induced secondary brain injury via the P38-MAPKAP2-Hsp27 pathway.