Introduction: Classical homocystinuria is a genetic disease caused by partial or total deficiency of cystathionine-β synthase (CβS) enzyme activity, ultimately leading to brain alterations and early atherosclerotic disease. Currently, there is no cure for the disease and the treatments consist in reducing homocysteine levels through diet, however not all patients respond to therapy. Due to its ability to increase neurotrophins production and decrease oxidative stress in the brain, environmental enrichment (EE) has been used with success as an adjuvant non-pharmacological therapy for CNS disorders. Here, we investigated the effects of 4 weeks enriched environment in a severe chronic chemically-induced model of hyperhomocysteinemia (HHCY) in Wistar rats.

Methods: Animals of both sexes were subjected to homocysteine administration subcutaneously (12 h intervals) from day 6 of life (P6) to P28. After this period, animals were continuously exposed to the enriched environment (or standard cages) for 30 days. Animals were tested for cognition and locomotor abilities and hippocampi were collected for the assessment of oxidative stress and histological damage.

Results: Animals in the HHCY group showed impaired learning in the reference memory assessment in the Morris water maze with no effects in the novel objects recognition test. HHCY did not impair locomotion in the open field nor in the horizontal ladder task. HHCY rats presented decreased hippocampal volume reversed by EE. Enrichment was also able to reverse cognitive impairments in the spatial memory, improve coordination in the ladder walking and recognition memory in the NOR test. HHCY altered redox balance, with no protective effects of EE.

Conclusions: Due to its benefits and no side effects reported in literature, EE can be suggested as potential complimentary therapy to improve memory and motricity impairments in homocystinuric patients, however the mechanisms involved in this neuroprotection needs further investigation.