Neuroprotective properties of a thiazolidine-2,4-dione derivative as an inhibitory agent against memory impairment and phosphorylated tau: In vitro and in vivo investigations

[Display omitted] •TZ4C treatments alleviated methamphetamine-induced taupathy in SH-SY5Y cells.•TZ4C improved learning and memory deficits in scopolamine-induced rats.•TZ4C decreased AChE activity in the hippocampus of scopolamine-induced rats.•TZ4C significantly reduced the level of p-Tau in the hippocampus of male Wistar rats.•TZ4C reduced cleaved caspase-3/procaspase-3 protein levels both in vitro and in vivo. Alzheimer’s disease (AD) is the most common form of neurodegeneration that results in memory disorders and cognitive impairment. The present study investigated the neuroprotective effects of the synthesized thiazolidine-2,4-dione derivative, (E)-5-(4-chlorobenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ4C), an inhibitor of p-Tau and memory impairment, using a SH-SY5Y cell model of methamphetamine-induced tauopathy and a scopolamine-induced memory impairment model in Wistar rats. In the present study, the neuroprotective effect of TZ4C was studied in a SH-SY5Y cellular model of methamphetamine-induced (2 mM) tauopathy and a scopolamine-induced (1.5 mg/kg/day) memory impairment model in male Wistar rats (n = 48). The memory functions and learning abilities of the rats were evaluated using the Morris water maze (MWM) and passive avoidance tests. Additionally, AChE activity in the rat hippocampus was quantified, and the expression of p-Tau, HSP70, and caspase-3 in both in vitro and in vivo samples was evaluated through Western blot analysis. TZ4C (0.1–1000 µM) did not exhibit significantly toxic effects on SH-SY5Y cell viability. Western blot results indicated that TZ4C led to reduced expression of p-Tau, HSP70, and cleaved caspase-3 in SH-SY5Y cells (3 and 10 µM) and the rat hippocampus (2 and 4 mg/kg). Additionally, the findings suggested that TZ4C enhanced memory function in rats with scopolamine-induced impairment and decreased acetylcholinesterase (AChE) specific activity. The comprehensive analysis of in vitro and in vivo experiments underscores the neuroprotective potential (improved neuropathology and reduced memory impairment) of TZ4C. These findings highlight the promise of TZ4C as a candidate for drug discovery programs to identify effective therapies for AD.