Dynamically visualizing the effects of rTMS on GCPII repair after ischemic stroke by [68Ga]Ga-PSMA-11 PET/CT.

BACKGROUND

Glutamate excitotoxicity driven by pathological upregulation of glutamate carboxypeptidase II (GCPII) and consequent depletion of neuroprotective metabotropic glutamate receptor 3 (mGluR3) constitutes a critical cascade underlying post-ischemic neuronal injury. Repetitive transcranial magnetic stimulation (rTMS) benefits post-stroke rehabilitation and modulates glutamatergic neurotransmission, but the underlying molecular mechanisms remain incompletely understood.

OBJECTIVE

To evaluate [68Ga]Ga-PSMA-11 PET/CT for quantifying GCPII expression dynamics after ischemic stroke, and to determine whether high-frequency rTMS confers neuroprotection by modulating the GCPII/mGluR3 axis.

METHODS

Primary rat astrocytes underwent oxygen-glucose deprivation/reperfusion (OGD/R) and 20 Hz rTMS in vitro. GCPII expression and [68Ga]Ga-PSMA-11 uptake were assessed by immunofluorescence and gamma counting. A rat model of middle cerebral artery occlusion (MCAO) was established, and longitudinal microPET/CT was performed in sham-operated controls (day 0) and in MCAO animals on days 3, 7, 14, and 21 post-surgery. GCPII and mGluR3 expression was validated by immunohistochemistry and Western blotting. Neurological recovery in the modeled rats was assessed by the modified Neurological Severity Score (mNSS) and rotarod test.

RESULTS

OGD/R upregulated GCPII and [68Ga]Ga-PSMA-11 uptake in astrocytes, attenuated by rTMS (p < 0.01). In MCAO rats, ipsilateral PET signal peaked on day 7, correlating positively with GCPII (R2 = 0.9101, 0.7717) and inversely with mGluR3 (R2 = 0.7982). rTMS improved mNSS and rotarod performance, reduced ipsilateral PET signal (p < 0.0001), and restored mGluR3 expression.

CONCLUSIONS

[68Ga]Ga-PSMA-11 PET/CT enables longitudinal in vivo GCPII mapping after ischemic stroke. High-frequency rTMS may promote recovery by suppressing GCPII overexpression and restoring mGluR3 neuroprotection, identifying a novel molecular mechanism underlying rTMS efficacy.