Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model.

ABSTRACT

Rapamycin (RAPA) is found to have neuro-protective properties in various neuroinflammatory pathologies, including brain aging. With magnetic resonance imaging (MRI) techniques, we investigated the effect of RAPA in a lipopolysaccharide (LPS)-induced inflammaging model in rat brains. Rats were exposed to saline (control), or LPS alone or LPS combined with RAPA treatment (via food over 6 weeks). Arterial spin labeling (ASL) perfusion imaging was used to measure relative cerebral blood flow (rCBF). MR spectroscopy (MRS) was used to measure brain metabolite levels. Contrast-enhanced MRI (CE-MRI) was used to assess blood-brain barrier (BBB) permeability. Immunohistochemistry (IHC) was used to confirm neuroinflammation. RAPA restored NF-κB and HIF-1α to normal levels. RAPA was able to significantly restore rCBF in the cerebral cortex post-LPS exposure (p < 0.05), but not in the hippocampus. In the hippocampus, RAPA was able to restore total creatine (Cr) acutely, and N-acetyl aspartate (NAA) at 6 weeks, post-LPS. Myo-inositol (Myo-Ins) levels were found to decrease with RAPA treatment acutely post-LPS. RAPA was also able to significantly restore the BBB acutely post-LPS in both the cortex and hippocampus (p < 0.05 for both). RAPA was found to increase the percent change in BOLD signal in the cortex at 3 weeks, and in the hippocampus at 6 weeks post-LPS, compared to LPS alone. RAPA treatment also restored the neuronal and macro-vascular marker, EphB2, back to normal levels. These results indicate that RAPA may play an important therapeutic role in inhibiting neuroinflammation by normalizing brain vascularity, BBB, and some brain metabolites, and has a high translational capability.