Administration of adenosine receptor agonists or antagonists after controlled cortical impact in mice: effects on function and histopathology.
Adenosine is an endogenous neuroprotectant via anti-excitotoxic effects at A(1) receptors, and blood flow promoting and anti-inflammatory effects at A(2a) receptors. Previous studies showed improved motor function after fluid percussion injury (FPI) in rats treated with the broad-spectrum adenosine receptor agonist 2-chloroadenosine (2-CA). We studied the effects of 2-CA, a specific A(1) agonist (2-chloro-N(6)-cyclopentyladenosine, CCPA), and a specific A(1) antagonist (8-cyclopentyl-1,3-dipropylxanthine, DPCPX) on motor task and Morris water maze (MWM) performance, and histopathology (contusion volume, hippocampal cell counts) after controlled cortical impact (CCI) in mice. Each agent (12 nmol), or respective vehicle (saline or DMSO) was injected into dorsal hippocampus beneath the contusion immediately after CCI or craniotomy (sham). 2-CA treatment attenuated wire grip deficits after CCI (P<0.05 versus other treatments). DPCPX treatment exacerbated deficits on beam balance (P<0.05 versus sham). No treatment effect was seen on MWM performance, although there was a deleterious effect of the DMSO vehicle used for DPCPX. Contusion volume tended to be attenuated by 2-CA (P=0.08 versus saline) and increased after either DMSO or DPCPX (P<0.05 versus all groups). CA1 and CA3 counts were decreased in all groups versus sham. However, treatment with the selective A(1) agonist CCPA attenuated the CA3 cell loss (P<0.05 versus other treatment). We suggest that the beneficial effect of the broad spectrum adenosine receptor agonist 2-CA on motor function after CCI is not mediated solely by effects at the A(1) receptor.
Varma
Manu R
MR
Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Dixon
C Edward
CE
Jackson
Edwin K
EK
Peters
Grant W
GW
Melick
John A
JA
Griffith
Raymond P
RP
Vagni
Vincent A
VA
Clark
Robert S B
RS
Jenkins
Larry W
LW
Kochanek
Patrick M
PM
D015762:2-Chloroadenosine / Q000627:therapeutic use; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology*; D002452:Cell Count; D002540:Cerebral Cortex / Q000293:injuries* / Q000473:pathology*; D018737:Hand Strength; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D014970:Xanthines / Q000627:therapeutic use
D018696:Neuroprotective Agents; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D015762:2-Chloroadenosine; C058394:2-chloro-N(6)cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine