Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice.
We reported that adenosine A(1) receptor (A(1)AR) knockout (KO) mice develop lethal status epilepticus after experimental traumatic brain injury (TBI), which is not seen in wild-type (WT) mice. Studies in epilepsy, multiple sclerosis, and neuro-oncology suggest enhanced neuro-inflammation and/or neuronal death in A(1)AR KO. We hypothesized that A(1)AR deficiency exacerbates the microglial response and neuronal damage after TBI. A(1)AR KO and WT littermates were subjected to mild controlled cortical impact (3 m/sec; 0.5 mm depth) to left parietal cortex, an injury level below the acute seizure threshold in the KO. At 24 h or 7 days, mice were sacrificed and serial sections prepared. Iba-1 immunostaining was used to quantify microglia at 7 days. To assess neuronal injury, sections were stained with Fluoro-Jade C (FJC) at 24 h to evaluate neuronal death in the hippocampus and cresyl violet staining at 7 days to analyze cortical lesion volumes. We also studied the effects of adenosine receptor agonists and antagonists on (3)H-thymidine uptake (proliferation index) by BV-2 cells (immortalized mouse microglial). There was no neuronal death in CA1 or CA3 quantified by FJC. A(1)AR KO mice exhibited enhanced microglial response; specifically, Iba-1 + microglia were increased 20-50% more in A(1)AR KO versus WT in ipsilateral cortex, CA3, and thalamus, and contralateral cortex, CA1, and thalamus (p < 0.05). However, contusion and cortical volumes did not differ between KO and WT. Pharmacological studies in cultured BV-2 cells indicated that A(1)AR activation inhibits microglial proliferation. A(1)AR activation is an endogenous inhibitor of the microglial response to TBI, likely via inhibition of proliferation, and this may represent a therapeutic avenue to modulate microglia after TBI.
Haselkorn
M Lee
ML
Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Shellington
David K
DK
Jackson
Edwin K
EK
Vagni
Vincent A
VA
Janesko-Feldman
Keri
K
Dubey
Raghvendra K
RK
Gillespie
Delbert G
DG
Cheng
Dongmei
D
Bell
Michael J
MJ
Jenkins
Larry W
LW
Homanics
Gregg E
GE
Schnermann
Jurgen
J
Kochanek
Patrick M
PM
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000473:pathology
D006131:Growth Inhibitors; D043682:Receptor, Adenosine A1; D000241:Adenosine