p,p′-Methoxyl-diphenyl diselenide protects against amyloid-β induced cytotoxicity in vitro and improves memory deficits in vivo

• p,p′-Methoxyl-diphenyl diselenide [(MeOPhSe)2] protected against amyloid-β induced cytotoxicity.
• (MeOPhSe)2 prevented Aβ-induced cell death by inhibiting apoptosis and downregulating JNK phosphorylation.
• (MeOPhSe)2 treatment attenuated Aβ-induced memory deficits in mice.

Behavioral evidence suggests that the organoselenium compound p,p′-methoxyl-diphenyl diselenide [(MeOPhSe)2] ameliorates memory and learning performance in rodents. Here, we investigated the molecular mechanism of (MeOPhSe)2 neuroprotection in cortical neurons exposed to amyloid-β (Aβ) peptide as well as in Aβ-infused mice. For this purpose, primary cultures of rat cortical neurons were pre-incubated with 10 μM of (MeOPhSe)2 or vehicle, followed by exposure to 25 μM Aβ fragment 25–35 or vehicle. Furthermore, the therapeutic effect of (MeOPhSe)2 (5 mg/kg, oral route, daily for 5 days) on memory deficits was evaluated in mice exposed to Aβ fragment 25–35 (3 nmol/3 μl/per site, intracerebroventricular infusion). The results demonstrate that (MeOPhSe)2 prevented Aβ-induced cell death in vitro, associated with inhibition of caspase-3 and -9 activities, poly (ADP-ribose) polymerase (PARP) cleavage and c-Jun N-terminal kinase (JNK) activation. Further, (MeOPhSe)2 rescued Aβ-induced memory impairment in mice. In conclusion, (MeOPhSe)2 is neuroprotective in vitro and in vivo, suggesting that this organoselenium compound offers a potential treatment option for Alzheimer’s disease.