# GTS-21

GTS-21 (DMXBA or DMBX-anabaseine) is a drug that has been shown to enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.
It is a derivative of the natural product anabaseine that acts as a partial agonist at neural nicotinic acetylcholine receptors (nAChRs). It binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent. Activation of the α7 nAChR has been shown to have neuroprotective effects and to improve cognitive function, making it an attractive target for drug development.
Both GTS-21 itself and its demethylated active metabolite 4-OH-GTS-21 display nootropic and neuroprotective effects, and GTS-21 is being investigated for the treatment of Alzheimer's disease, nicotine dependence, and, most significantly, for schizophrenia.

## Animal studies

Several studies have investigated the effects of GTS-21 in various animal models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. In these studies, GTS-21 has been shown to have anti-inflammatory and neuroprotective effects, and to improve cognitive function.
A recent study investigated the cholinergic anti-inflammatory pathway (CAP) in rheumatoid arthritis (RA). They used the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 to study its role in reducing synovial inflammation in a mice model of collagen-induced arthritis (CIA). GTS-21 lessened inflammation and reduced monocyte infiltration into the synovium. This study highlights a new mechanism by which cholinergic signaling can mitigate synovial inflammation in RA.

## Clinical trials

Phase one of a clinical trial using DXMBA as a potential treatment for schizophrenia was completed in January of 2005. 12 non-smoking subjects diagnosed with schizophrenia each received 3 daily treatments. The treatments consisted of 150mg of DMXBA, with another dose of 75mg administered 2 hours later, 75mg of DXMBA, with another dose of 37.5mg administered 2 hours later, and a placebo treatment. The order of the doses was randomized over the 3-day course of the treatments. A P50 auditory-evoked test measured a significant effect on sensory gating, and a Repeatable Battery for Assessment of Neuropsychological Status test measured a significant effect on neurocognition. The subjects did not report any symptoms or side effects, however the leukocyte count of one subject decreased from slightly above normal on the placebo, to slightly below normal when administered the higher dose of DXMBA. After receiving no exposure to the drug, the subject's leukocyte count returned to normal 2 days later. This clinical trial untimely was discontinued during phase II. Several other trials focusing on a range of health issues including Alzheimer's, schizophrenia, autism, ADHD, and nicotine use were either discontinued or withdrawn.
Another study of GTS-21 in healthy volunteers found that the drug improved attention and memory performance.

### Actions of GTS-21 on renal function, injury and inflammation

BUN and creatinine levels in the blood are common indicators of kidney function. KIM-1 and NGAL in plasma and kidney tissue are biomarkers of acute/chronic kidney injury. In these experiments, we examine the ability of GTS-21 to attenuate the effects of T2DM on renal function, injury and inflammation. The db/db mice demonstrate a significant increase in plasma BUN (Fig. 1A) and creatinine (Fig. 1B) compared with db/+ mice (P < 0.05 vs. db/+ mice). In contrast, db/db mice treated with GTS-21 demonstrate significant reductions in plasma BUN and creatinine compared with db/db controls (P < 0.05 vs. db/db vehicle). The db/db mice also demonstrate higher levels of plasma and renal injury biomarkers KIM-1 (Fig. 1C,E) and NGAL (Fig. 1D,F) compared to db/ + vehicle controls. GTS-21 significantly attenuated the increase in plasma and renal KIM-1 and NGAL observed in the db/db mice (p < 0.05, vs. db/db vehicle).
IL-6 and HMGB-1 are inflammatory cytokines. Renal and plasma levels of these inflammatory markers were measured to assess the effects of GTS-21 on inflammation in the db/db mice. As shown in Fig. 2, db/db mice demonstrated increased plasma and renal IL-6 and HMGB-1 levels compared with db/+ mice. Treatment with GTS-21 significantly attenuated the elevations in IL-6 and HMGB-1 seen in the db/db mice (P < 0.05, Fig. 2). Collectively, these results provide evidence that α7nAChR activation plays an important role in improving kidney function, modulating renal injury and regulating renal inflammation in db/db mice.

## History

The laboratory name GTS-21 means that it is the 21st chemical compound created by Gainesville (University of Florida in Gainesville) and Tokushima (Taiho Pharmaceutical) Scientists. DMXBA – 3-2,4-dimethoxybenzylidene anabaseine.