Robust increase of the translocator protein 18 kDa (TSPO), demonstrated with radiotracer [¹²³I]CLINDE, in an adult rat model of Traumatic Brain Injury

Question
Traumatic brain injury (TBI) can result in long-term disability, but the mechanisms are not fully elucidated. Neuroinflammation is part of these secondary injury mechanisms, and is therefore regarded as a potential target for treatment and diagnostics employing molecular imaging techniques. TSPO, a protein in the mitochondrial membrane, is robustly upregulated in response to injury and neuroinflammation, making it a marker. We therefore hypothesize that TSPO is time-dependently upregulated after TBI. This was investigated in a rat model of TBI, employing the TSPO-selective and clinically relevant radioligand [¹²³I]CLINDE.
Methods
Adult male Sprague-Dawley rats were randomized into four groups (survival time: 6, 24, 72 h and 28 d). Animals were anaesthetized and subjected to either sham injury, craniotomy or mild-to-moderate (2 mm impact depth at 4 m/sec) controlled cortical impact injury (CCI). Drug/surgery-naïve animals were included in the study. Frozen coronal sections were cut and TSPO binding was assessed in the vicinity of the injury (M1 motor cortex, 3.5 mm posterior and +4.0 mm lateral to bregma) with in vitro autoradiography.
Results
Binding of [¹²³I]CLINDE was nearly uniform and displaceable (10 µMol/L PK1195) in the brains of naïve and sham-operated animals.
At 24 h, injured animals exhibited a significant increase in binding in the whole ipsilateral hemisphere (49%) and the ipsilateral M1 cortex (201%). Interestingly, CCI also resulted in an elevated binding in the contralateral M1 cortex (38%). [¹²³I]CLINDE binding was maximally increased at 72 h after CCI in the whole ipsilateral hemisphere (368 %) and M1 cortex (1076%). Again, TBI significantly increased binding in the contralateral whole hemisphere (29%) and M1 cortex (32%).
Craniotomy, without TBI, produced a significant increase in TSPO at 24 h in the ipsilateral M1 cortex (42%) and at 72h in the ipsilateral hemisphere (232%) and M1 cortex (598%). At 6 h and 28 d, [¹²³I]CLINDE binding was not significantly different between the groups.
Conclusions
[¹²³I]CLINDE binding, reflecting TSPO, was significantly increased after experimental TBI, which corresponds to the time-course of the inflammatory response. This makes [¹²³I]CLINDE a suitable radiotracer for the assessment brain injury in TBI and the monitoring of anti-inflammatory (pharmaco)therapies.