Prolonged sevoflurane exposure induces exaggerated and persistent cognitive decline in old rats with pre-existing impairment by increasing hippocampal mitochondrial dysfunction and apoptosis.

BACKGROUND

Postoperative neurocognitive disorders are common in older adults; whether prolonged volatile anesthesia causes persistent decline or amplifies preexisting vulnerability remains uncertain. We assessed whether sevoflurane exposure induces persistent cognitive impairment and hippocampal injury in young and aged rats, stratified by baseline cognitive status.

METHODS

Female Wistar Hannover rats comprised young adults (10-12 weeks; n = 40) or aged (>24 months; n = 82). Aged rats were classified as cognitively intact (n = 47) or impaired (n = 35) after Morris Water Maze (MWM) pre-screening. Animals received 2% sevoflurane (SEVO+) or oxygen/air (SEVO-) for 3-h. Spatial memory was assessed by MWM probe trials (days 7, 30, and 90), with retraining. Subsets were sacrificed 24-h after exposure (n = 6/group) for histopathology and immunohistochemistry; remaining rats were evaluated after final behavioral analysis.

RESULTS

SEVO caused transient memory impairment in young rats on day 7, resolving by day 30. In aged rats, effects were greater and more persistent, especially in cognitively impaired animals, with reduced target-quadrant preference, fewer crossings on days 7 and 30, and poor long-term retention. Acutely, SEVO increased hippocampal CA1 injury and elevated pro-apoptotic (Bax/Bcl-2, Cl-Cas-3) and mitochondrial/oxidative stress markers (Drp1, COX-IV, GPX1, Hsp60). Long-term, persistent CA1 pathology and elevated amyloid-β were most prominent in cognitively impaired aged rats.

CONCLUSIONS

Prolonged SEVO exposure was associated with brief cognitive disruption in young female adults but led to more persistent cognitive decline and hippocampal injury in older rats with pre-existing impairment, underscoring baseline cognitive vulnerability as a modifier of long-term anesthesia-associated neurocognitive outcomes and an important consideration in surgical/anesthetic risk management.