Temporal dynamics of cognitive and non-cognitive behavioral phenotypes and early redox alterations in the intracerebroventricular streptozotocin-rat model of sporadic Alzheimer's disease.

Abstract

The intracerebroventricular streptozotocin (ICV-STZ) model mimics sporadic Alzheimer's disease (sAD), yet its early multi-domain behavioral progression and underlying mechanisms remain poorly characterized. This study provides the first cross-sectional temporal profiling integrating behavioral and redox phenotypes, uncovering novel dynamics that enhance the model's translational value for prodromal sAD. Male Wistar rats received ICV-STZ (3&#x202f;mg/kg) or vehicle and were assessed at early (5-7 days), intermediate (43-45 days), and advanced (88-90 days) post-injection stages for pain-related behavior, glycemic status, locomotor/exploratory activity, memory, and brain glutathione (GSH) levels. ICV-STZ caused transient pain-like behavior (elevated Rat Grimace Scale scores, days 1-14), persistent body-weight deficit, and normoglycemia, supporting a centrally driven metabolic dysfunction. Open-field testing showed a tri-phasic pattern: reduced rearing at 5 days (p&#x202f;<&#x202f;0.0001), selective hyperactivity at 43 days (increased speed, p&#x202f;<&#x202f;0.05), and increased immobility at 88 days (p&#x202f;=&#x202f;0.036), suggesting a transition from behavioral suppression to apathy-like withdrawal. Spatial memory trended toward decline (p&#x202f;=&#x202f;0.078), while novel object recognition (NOR) was impaired at 7 days (p&#x202f;=&#x202f;0.033) and 90 days (p&#x202f;=&#x202f;0.037) but preserved at 45 days (p&#x202f;=&#x202f;0.915). Transient GSH depletion occurred in the hippocampus and prefrontal cortex at 7 days; higher early GSH levels were associated with better NOR performance (r&#x209b; = 0.76, p&#x202f;=&#x202f;0.015) and rearing (r&#x209b; = 0.70, p&#x202f;=&#x202f;0.043). These findings reveal early pain- and redox-modulated cognitive vulnerability, a mid-stage compensatory phase, and progressive decline, highlighting therapeutic windows for antioxidant or metabolic interventions in preclinical sAD research.