Bengtsson SK, Johansson M, Bäckström T, Wang M.
Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in AβPPSwePSEN1ΔE9 Mice.
J Alzheimers Dis. 2012 Jan 1;31(1):71-84.
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This report by Bengtsson and colleagues adds to the growing body of literature demonstrating that 1) more is not better, and 2) that dosing and regimen of administration really do matter. In this study, allopregnanolone was constantly infused (via ALZET mini-pumps) at levels that cause stress for three months in very young mice (2.5 months of age). Chronic constant infusion for three months with stress levels of a molecule known to increase GABAergic function/inhibition in brain predictably had a negative impact on brain function required for learning and memory. This finding replicates what others have found with another and classic GABAergic modulator, benzodiazepine. Results of this investigation do replicate what has been known for many, many years—that persons chronically treated with high levels of anti-seizure medications have learning and memory deficits. Further, in the normally functioning stress response, allopregnanolone is generated to deactivate or turn off the brain stress system, which is every bit as necessary as activating the system. Thus, it may come as no surprise that chronic exposure to stress levels of a factor required for deactivating the stress response does, in fact, decrease brain activity.
Earlier analyses of allopregnanolone dose and treatment regimens demonstrated that allopregnanolone at a sub-sedative dose given either once per month, or once per week, significantly increased neurogenesis and learning and memory function, whereas a treatment regimen of every other day for three months decreased neurogenesis but also decreased β amyloid. Subsequent work to determine the optimal treatment regimen at which allopregnanolone increased neurogenesis and simultaneously decreased β amyloid burden indicated that a once-per-week treatment regimen was optimal to achieve both therapeutic goals.
These analyses provide important insights into therapeutic regimens targeting the regenerative response in the brain. More is not better. Further, it is an important reminder that, for a factor that under normal on/off exposure conditions has benefits, constant infusion of the same factor at elevated doses will not replicate benefits. Nor should we expect it.
The contribution of Bengtsson and colleagues reminds us again that dose and treatment regimens are critical aspects of the preclinical translation research landscape. For therapeutics targeting Alzheimer's and other neurodegenerative diseases, the "antibiotic" approach to treatment—that more for longer is better—needs to be seriously reconsidered.
Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD.
Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503.
Singh C, Liu L, Wang JM, Irwin RW, Yao J, Chen S, Henry S, Thompson RF, Brinton RD.
Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice.
Neurobiol Aging. 2011 Jul 29;
Chen S, Wang JM, Irwin RW, Yao J, Liu L, Brinton RD.
Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.
PLoS One. 2011;6(8):e24293.
Wang JM, Johnston PB, Ball BG, Brinton RD.
The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression.
J Neurosci. 2005 May 11;25(19):4706-18.