Novel Sigma Receptor Ligand Enhances Memory and Mitigates Microglia Proliferation

Sigma receptor 1 (Sig1R) and 2 (Sig2R) are expressed in central nervous system, in neurons and microglia. Modulation of these receptors has been identified for the treatment of inflammatory and neurodegenerative disorders, including Alzheimer's disease (AD). This research evaluated the impact of BBZI, a novel pan‐selective Sig1R‐Sig2R ligand in mouse models of Alzheimer's disease and microglia activation. BBZI has high affinity Sig1R‐Sig2R (Sig1R: Ki=0.8nM; Sig2R: Ki=2.5nM), with 100‐fold selectivity over a panel of 30 other receptors. Twelve‐month old Senescence Accelerated Mouse Prone‐8 (SAMP8) and 3xTg AD mice were treated with BBZI (i.c.v.) across a dosing range (0, 0.001, 0.01, 0.1, 1.0μg), and assessed for memory response via T‐maze. BBZI was also evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS). After plating for 24hrs, cells were treated for 24hrs with BBZI (0, 10, 100, 1000nM) against LPS (0, 10, 100ng/mL). Alamar Blue (cellular proliferation) and nitrite (surrogate of nitric oxide) output in media. BBZI significantly enhanced memory in SAMP8 mice at both 0.001μg and 0.01μg doses (p<0.01), and in 3xTg mice at 0.01μg dose (p<0.05), compared to vehicle controls. The mean percent reduction of alamar blue decreased with increasing concentrations of BBZI (p<0.05). The mean percent reduction of alamar blue was significantly lower for 1000nM BBZI compared to 0nM BBZI (p<0.05). No significant difference in nitrite level was observed with increasing concentrations of BBZI (p=0.65). These results identify pan‐selective Sig1R‐Sig2R ligand capacity to enhance memory in two age mouse models of AD, with further capacity to impact of microglial proliferation. Such a pan‐selective ligand shows viability for treatment of cognitive and neurodegenerative conditions. Support or Funding Information This work was supported by the School of Pharmacy, Southern Illinois University Edwardsville. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .