Therapeutic potential of SSZ in modulating Alzheimer’s disease pathology: A multi-targeted experimental approach

Alzheimer’s disease (AD) is a common neurological disorder marked by progressive cognitive decline and memory loss, and it remains a major global health concern due to the limited effectiveness of current symptomatic treatments. This study used SSZ, a novel, chemically synthesized compound featuring pyrrolopyridine and N-cyclohexyl groups, designed as a multi-targeted inhibitor with anti-AD pharmacophore properties. We investigated the therapeutic potential of SSZs using an experimental rat model of AD produced by amyloid-beta (Aβ). SSZ demonstrated substantial pharmacological activity by targeting key enzymes implicated in AD pathogenesis, including BACE-1, gamma-secretase, MAO-B, and acetylcholinesterase. In addition, SSZ therapy demonstrated neuroprotective benefits by significantly reducing apoptotic markers (Bax, caspase-3) and upregulating the anti-apoptotic protein Bcl-2. This compound also restored myelin basic protein (MBP) levels and reduced pathological markers such as neurofilament light chain (NEFL) and microtubule-associated protein (MAP). Moreover, SSZ increased antioxidant defences, such as glutathione (GSH) and superoxide dismutase (SOD), decreased oxidative stress markers, such as lactate dehydrogenase (LDH), nitric oxide (NO), and malondialdehyde (MDA), and regulated inflammatory cytokines, such as TNF-α and IL-1β. Notably, SSZ restored neurotransmitter levels, dopamine, acetylcholine, and glutamate, essential for cognitive function. Histopathological analyses revealed that SSZ mitigated neuronal and myelin damage across critical brain regions, including the midbrain, hippocampus, and cortex. When combined with standard treatments such as donepezil and memantine, SSZ demonstrated synergistic effects, further enhancing its therapeutic efficacy. These results highlight SSZ’s potential as a multi-targeted therapeutic option to combat AD pathogenesis and improve therapy approaches.