GPI-5693

Wearing a silicone wristband exposes the internal surface of the wristband to glucose, lipids, and metabolites (metabolome) found in sweat and the external surface to occupational and environmental factors that could impact health found in the air (exposome). We use silicone wristband electrospray ionization mass spectrometry (SWESI‐MS) to monitor these species. A 20‐μL drop of a (1 : 1, v/v) water:methanol solution is sufficient to extract abundant metabolites and contacting chemicals derived from ingestion of drink, smoke, diet, drug, and air pollution exposure. A wide coverage of species is successfully detected and identified from a worn wristband including caffeine, glucose, nicotine, reserpine, lactate, phosphocreatinine, oleic acid, and urea. The signal from a triangular wristband surface triggered by applying a voltage of 5 kV to form a spray remains stable for at least 2 minutes. The response is linear from 10 pM to 100 μM. The SWESI‐MS method offers the advantages of onsite sampling, no preprocessing, simple testing, and automatic high‐dimensional data searching. It can be used for simultaneously monitoring hazardous chemical contamination and abnormal expression of sweat‐secreted metabolites that are indicative of some physiological condition.

Glutamate carboxypeptidase II (GCPII), localized on the surface of astrocytes and activated microglia, regulates extracellular glutamate concentration in the central nervous system (CNS). We have previously shown that GCPII is upregulated in activated microglia in the presence of inflammation. Inhibition of GCPII activity could reduce glutamate excitotoxicity, which may decrease inflammation and promote a 'normal' microglial phenotype. 2-(3-Mercaptopropyl) pentanedioic acid (2-MPPA) is the first GCPII inhibitor that underwent clinical trials. Unfortunately, immunological toxicities have hindered 2-MPPA clinical translation. Targeted delivery of 2-MPPA specifically to activated microglia and astrocytes that over-express GCPII has the potential to mitigate glutamate excitotoxicity and attenuate neuroinflammation. In this study, we demonstrate that 2-MPPA when conjugated to generation-4, hydroxyl-terminated polyamidoamine (PAMAM) dendrimers (D-2MPPA) localize specifically in activated microglia and astrocytes only in newborn rabbits with cerebral palsy (CP), not in controls. D-2MPPA treatment led to higher 2-MPPA levels in the injured brain regions compared to 2-MPPA treatment, and the extent of D-2MPPA uptake correlated with the injury severity. D-2MPPA was more efficacious than 2-MPPA in decreasing extracellular glutamate level in ex vivo brain slices of CP kits, and in increasing transforming growth factor beta 1 (TGF-β1) level in primary mixed glial cell cultures. A single systemic intravenous dose of D-2MPPA on postnatal day 1 (PND1) decreased microglial activation and resulted in a change in microglial morphology to a more ramified form along with amelioration of motor deficits by PND5. These results indicate that targeted dendrimer-based delivery specifically to activated microglia and astrocytes can improve the efficacy of 2-MPPA by attenuating glutamate excitotoxicity and microglial activation.