Abstract
Gliosis is implicated in the pathophysiology of many neuropsychiatric diseases, including treatment-resistant major depressive disorder (TRD). Translocator protein total distribution volume (TSPO VT), a brain marker mainly reflective of gliosis in disease, can be measured using positron emission tomography (PET). Minocycline reduces gliosis and translocator protein binding in rodents, but this is not established in humans. Here, the ability of oral minocycline to reduce TSPO VT was assessed in TRD. To determine whether oral minocycline, as compared to placebo, can reduce prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula TSPO VT in TRD, twenty-one TRD participants underwent two [18F]FEPPA PET scans to measure TSPO VT. These were completed before and after either oral minocycline 100 mg bid or placebo which was administered in a randomized double-blinded fashion for 8 weeks. There was no significant difference between the minocycline and placebo groups on change in TSPO VT within the PFC, ACC, and insula (repeated measures ANOVA, effect of group interaction, PFC: F1,19 = 0.28, P = 0.60; ACC: F1,19 = 0.54, P = 0.47; insula F1,19 = 1.6, P = 0.22). Oral minocycline had no significant effect on TSPO VT which suggests that this dosage is insufficient to reduce gliosis in TRD. To target gliosis in TRD either alternative therapeutics or intravenous formulations of minocycline should be investigated. These results also suggest that across neuropsychiatric diseases in humans, it should be assumed that oral minocycline will not reduce TSPO VT or gliosis unless empirically demonstrated.
Highlights
In the pathophysiology of several burdensome, frequently treatment-resistant neuropsychiatric diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, obsessive compulsive disorder, and major depressive disorder (MDD), an inflammatory response of a gliosis composed of activation and Attwells et al Translational Psychiatry (2021)11:334 models suggest that minocycline has an important translational application to target gliosis, it has not been definitively demonstrated that minocycline affects gliosis in human neuropsychiatric diseases.Translocator protein (TSPO) is expressed in activated microglia, activated astroglia, and endothelial cells
The differential elevation of TSPO binding in neuropsychiatric disease as compared to health is usually attributed to the greater activation and proliferation of TSPO-positive microglia and astroglia that occur during gliosis[2,14]
We evaluated the effect of minocycline on TSPO VT as measured with [18F] FEPPA positron emission tomography (PET) in treatment-resistant major depressive episodes (MDE) of MDD14. [18F]FEPPA has excellent properties including high, selective affinity for TSPO20, increased binding during induced neuroinflammation[21], no detectable radioactive metabolites in brain in preclinical assessment[22] and a high ratio of specific binding relative to free and non-specific binding[22,23]
Summary
Translocator protein (TSPO) is expressed in activated microglia, activated astroglia, and endothelial cells. In rodent models of gliosis after LPS administration, toxin, and stroke, overall TSPO binding is strongly related to its magnitude of expression in activated microglia[8,9,10]. In human neuropsychiatric illnesses, such as AD, HIV encephalitis, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and stroke, TSPO is expressed mainly in activated microglia and to a lesser extent in astroglia[11,12,13]. Most TSPO expression is consequent to its presence in endothelial cells. The differential elevation of TSPO binding in neuropsychiatric disease as compared to health is usually attributed to the greater activation and proliferation of TSPO-positive microglia and astroglia that occur during gliosis[2,14]
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