Background and ObjectivesAlzheimer’s disease (AD) is the most common form of dementia among older persons. Thymoquinone (TQ) has anti-inflammatory, anticonvulsant and antioxidant activity. A novel α7 nicotinic acetyl choline receptor (α7 nAChR ) agonist (PNU- 282987) have been identified to enhance the cognitive performance. An alternative treatment strategy via compounds known as nicotinic “positive allosteric modulators” (PAMs) has been reported. This study was designed to investigate the combination of PAM of α7 nAChRs with PNU- 282987 or with TQ as a possible treatment for AD in rat.Methods48 male albino rats were divided into 4 groups. Group I (Control), Group II received lipopolysaccharide, 0.8 mg/kg by intraperitoneal injection (IPI) once, Group III received TQ 10 mg/kg by IPI, Group IV received PNU-120596 1 mg/kg by IPI, in addition to PNU-282987 1 mg/kg by IPI in subgroup IVa and TQ in subgroup b. All treatment drugs were given for 5 days.ResultsAcidophilic masses, deformed neurons, Congo red +ve masses and reduced Phospho-CREB immunoexpression were seen in group II. All changes regressed by treatment. Some CD44 +ve cells were noticed in group II and few +ve cells in subgroup IVa, that became multiple in group III and subgroup IVb. The histological, histochemical and immunohistochemical changes were confirmed statistically and significant differences were recorded.ConclusionsTQ or α7 nAChR agonist combined with PAM can have an important role in treatment of AD that is superior to thymoquinone alone. Exceptionally, TQ single or combined with PAM proved activation of MSC.