Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Thymoquinone (TQ) is the active component of black seeds with many health benefits. Intermittent fasting (IF) is a dietary pattern with antioxidant and neuro-regenerative effects. This study explored the neuroprotective potential of TQ, IF or their combination on hippocampus of AD-like rat model with emphasis on the underlying mechanisms as neurogenesis and autophagy. Eighty adult male rats were divided into 7 groups: control, TQ given TQ (50 mg/kg/day orally), IF underwent IF for 14 h/day, AL given Aluminum chloride (AlCl3) (300 mg/kg/day orally) to induce AD-like pathology, AL + TQ, AL + IF and AL + TQ+ IF for 4 weeks. AD-like pathology was evaluated by behavioral tests, histopathology, immunostaining for apoptosis (Bax), microglia (CD68) and neurogenesis (nestin). Expressions of p-Tau, oxidative stress & autophagy markers (P62 and LC3B II) were assessed by western blot. AL group showed histological and ultrastructural AD-like features as apoptotic neurons, amyloid β deposition, significant elevation in MDA, p-Tau and P62, reduction in SOD and LC3B II, upregulation of Bax immune-expression and number of CD68 + activated microglia and diminished nestin positive cell number. TQ and IF mitigated these changes particularly when used in combination. In conclusion, TQ and IF protect against AlCl3-induced hippocampal AD-like pathology through reduction of oxidative stress, apoptosis, amyloid deposits, p-Tau expression and their modulatroy effects on microglia activation, neurogenesis and autophagy. The neuroprotective potential of IF is superior to TQ, while the optimal neuroprotection is achieved by the combination of both.
