Caffeic Acid Mitigates L-Methionine-Induced Impairment of Hippocampal Neural Stem Cells Through Anti-Apoptotic Signaling in Adult Rats

Chronic administration of L-methionine (L-met) induces hyperhomocysteinemia, which triggers oxidative stress, impairs hippocampal neurogenesis and ultimately causes cognitive decline. Caffeic acid (CA) has been reported to exert neuroprotective effects through its antioxidant properties, attenuating oxidative damage in the brain, promoting hippocampal neurogenesis, and improving cognitive function. This study evaluated the neuroprotective efficacy of CA against L-met-mediated hyperhomocysteinemia and associated hippocampal neurotoxicity in a rat model. Twenty-four male Sprague-Dawley rats were randomly divided into four groups (n = 6/group): Vehicle, L-met (1.7 g/kg), CA (40 mg/kg), and CA + L-met. Treatments were administered orally once daily for 28 days. Immunofluorescence analysis revealed that CA effectively prevented L-met-induced depletion of nestin-positive cells. Structural assessments further confirmed that CA counteracted tissue atrophy, preserving the anatomical volumes of both the dentate gyrus (DG) and granule cell layer (GCL). Furthermore, CA attenuated the L-met-induced downregulation of the neurogenesis-related proteins nestin and Notch-1 in the hippocampus. Notably, CA also modulated apoptosis-related protein expression by reducing Bax and Caspase-3 levels while upregulating Bcl-2 expression. In conclusion, CA was associated with protection against L-met-induced alterations in hippocampal neurogenesis- and apoptosis-related protein expression, as well as preservation of hippocampal architecture, in this experimental model.