2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Brain-Injuries

The bone marrow-derived cell (BMDC)-associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A2A receptor (A2AR) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A2AR exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid-induced ALI model (a nonneurogenic ALI model.) Moreover, the A2AR agonist CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A2AR and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C-protein kinase C signaling, which mediated the proinflammatory effect of A2AR. These results are in striking contrast to the well-known antiinflammatory and protective role of A2AR in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A2AR.

Topics: Acute Lung Injury; Adenosine; Adenosine A2 Receptor Agonists; Adult; Animals; Bone Marrow Cells; Brain Injuries; Disease Models, Animal; Female; Glutamic Acid; Humans; Male; Mice; Mice, Knockout; Middle Aged; Phenethylamines; Protein Kinase C; Receptor, Adenosine A2A; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Signal Transduction; Triazines; Triazoles; Type C Phospholipases

Traumatic brain injury (TBI) results in both focal and diffuse brain pathological features that become severely exacerbated after the initial injury. Owing to this disease complexity, no effective therapeutic measure has yet been devised aimed directly at these pathological processes. We developed a clinically relevant model of TBI and tested the bidirectional neuroprotective role of adenosine 2A receptors (A2ARs) at different times.. Wistar rats were divided into 4 treatment groups (sham, TBI, A2AR agonist [CGS-21680], and A2AR antagonist [SCH-58261]) and 4 post-TBI intervals (15 minutes and 1, 12, and 24 hours). A2AR agonist and antagonist effects were tested by the neurological functional score (NFS) and levels of cyclic adenosine monophosphate, interleukin-1β, oxidative stress antioxidant markers, and caspase-3.. The A2AR agonist-treated group showed significant NFS improvement at 15 minutes and 1 hour after TBI compared with the TBI group. However, no improvement was observed at 12 and 24 hours. The A2AR antagonists resulted in no NFS improvement at 15 minutes and 1 hour, and significant improvement observed at 12 and 24 hours. Significant neuroprotective effect with an A2AR agonist were observed with cyclic adenosine monophosphate, interleukin-1β, oxidative stress markers, catalase, and caspase-3 levels at 15 minutes and 1 hour after TBI. The A2AR antagonist showed no effect at these intervals but showed a protective effect at 12 and 24 hours after TBI.. The A2AR agonist showed a beneficial neuroprotective effect at the early stages after TBI, and the A2AR antagonist showed a benefit at the later stages after TBI. These findings suggest that A2AR agonists and antagonists should be used in accordance with the point at which the TBI occurred.

Topics: Adenosine; Animals; Brain Injuries; Brain Injuries, Traumatic; Disease Models, Animal; Male; Neuroprotection; Neuroprotective Agents; Phenethylamines; Pyrimidines; Rats, Wistar; Receptors, Purinergic P1; Signal Transduction; Time Factors; Triazoles

Recently, activation of the adenosine A2A receptors has been shown to exert protection against peripheral tissue injuries but aggravation in the central nervous system (CNS) injuries. To explore the different effects of adenosine A2A receptors and try to perform some new treatment strategies for peripheral tissue and CNS traumas, we constructed the mouse models of skin trauma, skin combined radiation-impaired wound and traumatic brain injury (TBI), respectively. Wild type mice and A2A receptor gene knockout mice were both used in the experiments. In skin trauma and combined radiation-impaired wound models, the time of wound healing was observed, while in TBI model, neurological deficit scores, water content in injured brain and glutamate concentration in cerebral spinal fluid (CSF) were detected at 24 h after TBI. The results showed that in skin trauma and combined radiation-impaired wound models, CGS21680 (an agonist of the A2A receptors) promoted while A2A receptor gene knockout delayed the course of skin wound healing. On the contrary, in TBI model, A2A receptor gene knockout, not CGS21680, showed a protective role by inhibition of glutamate release. These data further indicate that promoting glutamate release may account for the different effects of A2A receptor activation in CNS injury and peripheral tissue injury models. These findings may provide some experimental evidence and a new strategy for clinical treatment of peripheral tissue damages by agonists of A2A receptors, while treatment of CNS injuries by antagonists of A2A receptors.

Topics: Adenosine; Animals; Brain; Brain Injuries; Disease Models, Animal; Glutamic Acid; Mice; Mice, Knockout; Phenethylamines; Receptor, Adenosine A2A; Wound Healing

Hypoperfusion after traumatic brain injury may exacerbate damage. Adenosine, a vasodilator, regulates cerebral blood flow (CBF). Treatment with adenosine receptor agonists has shown benefit in experimental CNS trauma; however, their effects on CBF after injury remain undefined. We used magnetic resonance imaging to assess CBF in uninjured rats both early and at 24 h after intrahippocampal administration of either the nonselective adenosine receptor agonist 2-chloroadenosine (2-CA, 12 nmol) or the A(2A)-receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarbox-amidoadenosine (CGS 21680, 6 nmol). We also assessed the effects of these agents on cerebral metabolic rate for glucose (CMRglu). We then assessed the effect of 2-CA on CBF at 3.5 to 5 h after controlled cortical impact (CCI). Injection of 2-CA into uninjured rat brain produced marked increases in CBF in ipsilateral hippocampus and cortex versus vehicle (P<0.05); CBF increases persisted even at 24 h. Measurement of hippocampal levels of 2-CA showed persistent increases to 24 h. CGS 21680 produced even more marked global increases in CBF than seen with 2-CA (2-6-fold versus vehicle, P<0.05 in 10/12 regions of interest (ROIs)). Neither agonist altered CMRglu versus vehicle. After CCI, 2-CA increased CBF in ipsilateral hippocampal and hemispheric ROIs (P<0.05 versus vehicle), but the response was attenuated at severe injury levels. We report marked increases in CBF after injection of adenosine receptor agonists into uninjured rat brain despite unaltered CMRglu. 2-Chloroadenosine produced enduring increases in CBF in uninjured brain and attenuated posttraumatic hypoperfusion. Future studies of adenosine-related therapies in CNS injury should address the role of CBF.

Topics: 2-Chloroadenosine; Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Agonists; Animals; Antihypertensive Agents; Brain Injuries; Cerebrovascular Circulation; Magnetic Resonance Imaging; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Spin Labels; Trauma Severity Indices