Adenosine [A.sub.1] receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice

• Published in: Journal of neurotrauma Vol. 27; no. 5; p. 901
• Main Authors: Haselkorn, M. Lee, Shellington, David K, Jackson, Edwin K, Vagni, Vincent A, Janesko-Feldman, Keri, Dubey, Raghvendra K, Gillespie, Delbert G, Cheng, Dongmei, Bell, Michael J, Jenkins, Larry W, Homanics, Gregg E, Schnermann, Jurgen, Kochanek, Patrick M
• Format: Journal Article
• Language: English
• Published: Mary Ann Liebert, Inc 01.05.2010
• Subjects: Adenosine; Analysis; Animal experimentation; Brain; Brain cells; Gene expression; Injuries; Physiological aspects
• ISSN: 0897-7151; 1557-9042
• DOI: 10.1089/neu.2009.1075

We reported that adenosine [A.sub.1] receptor ([A.sub.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.sub.1]AR KO. We hypothesized that [A.sub.1]AR deficiency exacerbates the microglial response and neuronal damage after TBI. [A.sub.1]AR KO and WT littermates were subjected to mild controlled cortical impact (3m/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 ³H-thymidine uptake (proliferation index) by BV-2 cells (immortalized mouse microglial). There was no neuronal death in CA1 or CA3 quantified by FJC. [A.sub.1]AR KO mice exhibited enhanced microglial response; specifically, Iba-1 + microglia were increased 20-50% more in [A.sub.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.sub.1]AR activation inhibits microglial proliferation. [A.sub.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. Key words: adenosine; [A.sub.1] receptor; BV-2 cells; head injury; Iba-1; knockout; microglia; neurotrauma