Increased [18F]ASEM α7-nAChR binding in diffuse traumatic brain injury (TBI) is opposite to that in the focal TBI in rodent models.

Objectives The main objective of this project was to evaluate [18F]ASEM for PET imaging of α7-nAChR binding in the diffuse impact acceleration (IA) TBI model in rodents. Many lines of evidence suggest active involvement of α7-nAChRs in pathophysiological processes of TBI. In vitro α7-nAChR autoradiography studies demonstrated decreased binding in the brain of mice, rats and piglets with focal TBI. Our previous PET experiments with [18F]ASEM, a highly specific and selective clinical PET tracer for α7-nAChRs, demonstrated the reduction of α7-nAChR binding in the focal controlled cortical impact TBI model in rodents due to neuronal damage.

Methods [18F]ASEM PET imaging experiments (dynamic scans) were performed with an ARGUS small-animal PET/CT scanner (Sedecal, Madrid, Spain) in an IA-TBI model in mice. The following post-trauma intervals were evaluated: 3, 7, 14 and 31 days. Sham animals that were scanned side-by-side with IA mice were used for comparison to IA animals (n=4 for each group). Regional SUV values for the cortex, hippocampus, striatum, thalamus and cerebellum were generated and SUVTBI/ SUVsham ratio values were compared on different days post trauma. Immunofluorescence staining (dual labeling with anti-α7-nAChR antibody and another antibody from markers including either neuronal marker-NeuN, microglial markers - IBA1 and CD68 or astrocytal marker - GFAP) was performed in a separate set of sham and IA mouse brains (n=4 for each group).

Results In the PET experiments, a significant increase of SUVTBI values was observed on days 3 (40-60%) and 7 (15-30%) in the mouse brain regions in IA versus SUVsham, but there was no significant difference on days 14 and 31 (Fig). Similar results were also obtained in rat IA model. Immunofluorescence staining of the brain tissue demonstrated that microglia α7-nAChRs were present in the impact acceleration TBI mouse brain, but nearly absent on the sham mice.

Conclusions [18F]ASEM - PET experiments show transient increases (day 3) of α7-nAChR binding in the diffuse IA-TBI model in mice potentially due to expression of α7-nAChRs in the activated microglia. This study indicated that α7-nAChR might be involved differently in diffuse TBI (present study) than in focal TBI (previous studies).