Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects?
BACKGROUND
Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo.


METHODS
Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner).


RESULTS
A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes.


CONCLUSIONS
This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
G J
GJ
Moore
J M
JM
Bebchuk
K
K
Hasanat
G
G
Chen
N
N
Seraji-Bozorgzad
I B
IB
Wilds
M W
MW
Faulk
S
S
Koch
D A
DA
Glitz
L
L
Jolkovsky
H K
HK
Manji
D000328:Adult; D000704:Analysis of Variance; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects*; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies
D018696:Neuroprotective Agents; D001224:Aspartic Acid; C000179:N-acetylaspartate; D008094:Lithium