Metal protein attenuating compounds for the treatment of Alzheimer's dementia

UCL Mental Health Sciences Unit, University College Medical School, London, UK.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 01/2012; 5(2):CD005380. DOI: 10.1002/14651858.CD005380.pub4
Source: PubMed


The protein amyloid-β (Aß) is strongly implicated in the development of Alzheimer's dementia, where it aggregates in clumps causing damage and death of brain cells. This clumping is encouraged by copper and zinc (metal ions) in the brain. Metal protein attenuating compounds (MPACS) bind strongly to copper and zinc (this is known as chelation), both preventing the clumping together of Aß and promoting processes which may cause it to dissolve and so be cleared from brain cells. Therefore MPACS may be a potential therapy for Alzheimer's dementia. Two different types of MPAC have been used in clinical trials and the drugs are known as PBT1 and PBT2. The trial of PBT1 compared with placebo (in 36 patients) showed no statistically significant difference in cognition or memory between the active treatment and placebo groups at 36 weeks. We therefore conclude that there is no current evidence that treatment with clioquinol (PBT1) has any significant effect on cognition and in particular memory (as measured by the ADAS-Cog scale) in patients with Alzheimer's dementia. This drug has now been withdrawn from development. The trial of PBT2 showed it was safe after 12 weeks of treatment but demonstrated no overall significant effect on cognition or memory.

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    • "Hence, understanding how PKA is dysregulated in various neuronal subcompartments will help guide the development of future pharmacological therapies for reversing degeneration in various brain degenerative diseases. It is worth noting that the use of mitochondrially directed antioxidants, calcium chelators/metal proteinbinding compounds, N -methyl D-aspartate receptor inhibitors , and caspase inhibitors has been developed but has demonstrated modest to no benefit in clinical trials for treating various brain degenerative disorders ( Snow et al., 2010 ; Johansson et al., 2011 ; Bonelli and Wenning, 2006 ; Regland et al., 2001 ; Sampson et al., 2012 ). "
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