Thalidomide is a small molecule drug that is able to pass the blood-brain barrier and modulate how the immune system works.
The drug was originally used to treat morning sickness, but numerous instances of severe birth defects led to its withdrawal from the market. It was reintroduced, with a warning against its use during pregnancy or while breastfeeding, and is currently used for the treatment of a number of immunological and inflammatory disorders, as well as multiple myeloma and other types of cancers.
How thalidomide works
Thalidomide has a number of different effects including the suppression of the immune system, the inhibition of the growth of new blood vessels, and the inhibition of inflammation. The drug acts on various cytokines including tumor necrosis factor-alpha (TNFα), inhibiting its release from monocytes (a type of white blood cell involved in the immune system).
Thalidomide use in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by excessive amounts of amyloid β peptides (Aβ), which cause significant release of inflammatory factors, including TNFα in the brain. TNFα-mediated signaling pathway induces an enzyme called β amyloid cleavage enzyme 1 (BACE1), which is a key enzyme involved in the cleavage of APP resulting in Aβ production. It was therefore hypothesized that thalidomide may be beneficial for the treatment of AD.
A preclinical study in a mouse model of AD has shown that thalidomide is effective in inhibiting TNF-α, thereby reducing Aβ generation and improving learning and memory deficits.
Another preclinical study in a mouse model called the APP23 transgenic mice (used to study AD) has shown that long-term thalidomide treatment can reduce amyloid pathology (the formation of Aβ plaques) by inhibiting the expression of BACE1.
Thalidomide in clinical trials
The effect of thalidomide has only been tested in one clinical trial in AD but this failed to demonstrate a beneficial effect on cognition because the necessary dose of the drug was never reached due to adverse side effects.
This was a 24-week, randomized, double-blind, placebo-controlled, parallel group Phase 2 trial (NCT01094340) was conducted by Banner Sun Health Research Institute in Sun City, Arizona. It was designed to study the effect of an escalating dose regimen of thalidomide (with a target dose of 400 mg daily) on biomarkers such as BACE1 in the blood and the fluid surrounding the brain and spinal cord, in patients with mild to moderate AD.
A total of 185 patients were pre-screened, out of which 25 were recruited for the trial. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Among the 25 participants, 14 left the trial early due to adverse events. Those who completed the study never reached the target therapeutic dose of 400 mg per day due to reported adverse events. No cognitive differences were recorded between the treated and placebo groups at the end of the trial. The researchers concluded that AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose to have an effect on BACE1.
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