Folic Acid potentiates the effect of memantine on spatial learning and neuronal protection in an Alzheimer's disease transgenic model.
Folic acid deficiency and hyperhomocysteinemia potentiate amyloid-beta (Abeta) neuron toxicity. Memantine, an NMDA antagonist used in moderate to severe AD, is considered to be neuroprotective. We propose that folic acid might have a synergistic effect for memantine in protecting neurons from Abeta accumulation. We treated 8-month-old Tg2576 transgenic mice with memantine (30 mg/kg/day) with or without folic acid (8 mg/kg/day) for 4 months. Escape latencies in the Morris water maze were significantly shorter in the folic acid-memantine treatment group Tg(+)_M+F compared to both the non-treatment transgenic controls Tg(+) and the memantine-treatment group Tg(+)_M (both p < 0.05). Analysis of Abeta40 and Abeta42 showed lower brain loads in both treatment groups but this did not reach statistical significance. Histopathology analysis showed that Tg(+)_M+F had lower ratios of neuronal damage than Tg(+) (p < 0.001) and Tg(+)_M (p< 0.005). DNA analysis revealed that in the Tg(+)M_+F group, transcription was upregulated in 72 brain genes involved in neurogenesis, neural differentiation, memory, and neurotransmission compared to the Tg(+)_M group. In conclusion, we found that folic acid may potentiate the effect of memantine on spatial learning and neuronal protection. The benefit of combination therapy may be through co-action on the methylation-controlled Abeta production, and modification of brain gene expression.
Chen
Ta-Fu
TF
Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huang
Rwei-Fen S
RF
Lin
Sey-En
SE
Lu
Jyh-Feng
JF
Tang
Ming-Chi
MC
Chiu
Ming-Jang
MJ
D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014803:Vitamin B Complex / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014803:Vitamin B Complex; D005492:Folic Acid; D008559:Memantine