SMALL MOLECULE FTO INHIBITOR MO-I-500 AMELIORATES STREPTOZOTOCIN-INDUCED COGNITIVE DEFICIT IN MALE WISTAR RATS

The Fat mass and obesity-associated (FTO) protein is an RNA demethylase responsible for the demethylation of N6-methyladenosine (m⁶A) nucleosides and plays a key role in RNA metabolism, influencing brain development and disease. MO-I-500 is a well-characterized, blood-brain barrier-penetrating, FTO inhibitor with protective effects from oxidative stress and streptozotocin (STZ)-induced toxicity in neuronal and glial cultures. However, its potential neuroprotective effects in vivo are unknown.
Here, we evaluated MO-I-500 effects in the STZ model of sporadic Alzheimer’s disease (sAD) in male Wistar rats. Two bilateral intracerebroventricular (ICV) injections of STZ (3 mg/kg) were administered 48 hours apart. MO-I-500 treatment was split into two 5-day periods of daily intraperitoneal injections (10 mg/kg in 0.1% methylcellulose), starting 6 days prior to and 14-days after the ICV applications, respectively. Four weeks after STZ administration, Morris water maze (MWM) was performed. Subsequently, brains were collected to analyse expression of m⁶A pathway-related proteins and m⁶A enrichment in poly(A) mRNA.
STZ+vehicle group (n=9) demonstrated significant deficits in MWM compared to SHAM group (n=9) in escape latency (p<0.001) and target quadrant preference in the probe test (p=0.021). Compared to STZ+vehicle-treated, STZ+MO-I-500-treated rats (n=8) demonstrated shorter escape latencies (p=0.026) and quadrant preference (p=0.024). Our data thus demonstrate that MO-I-500 ameliorates STZ-induced cognitive deficit. Furthermore, a 34-day weight gain reduction observed in the STZ+veh was ameliorated by MO-I-500 (p=0.003).
Collectively, our data demonstrate the neuroprotective effects of MO-I-500 in an in vivo model of sAD. This work was supported by the Czech Science Foundation (grant No. 25-17745S).