Article

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). 05/2012; 5(2):CD005380. DOI: 10.1002/14651858.CD005380.pub4
Source: PubMed

ABSTRACT

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 This drug has now been withdrawn from development.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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    • "Among a handful of drugs that appear to inhibit Aβ 42 from forming toxic oligomers [6, 27, 32, 41,4950515253 in pilot studies, several have reached clinical trials. Indeed, trials of PBT1 (clioquinol), a metal chelator, which modulates affinity for Cu 2+ and Zn 2+ and inhibits metal-induced Aβ 42 aggre- gation [6, 54, 55] were dropped because of side effects [56]. PBT2, a second generation of PBT1, was safe but demonstrated no significant effect on cognition or memory in the trial (Pubmed Health, 2014 ). "

    Full-text · Article · Feb 2016
    • "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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    ABSTRACT: In neurons, enhanced protein kinase A (PKA) signaling elevates synaptic plasticity, promotes neuronal development, and increases dopamine synthesis. By contrast, a decline in PKA signaling contributes to the etiology of several brain degenerative diseases, including Alzheimer's disease and Parkinson's disease, suggesting that PKA predominantly plays a neuroprotective role. A-kinase anchoring proteins (AKAPs) are large multidomain scaffold proteins that target PKA and other signaling molecules to distinct subcellular sites to strategically localize PKA signaling at dendrites, dendritic spines, cytosol, and axons. PKA can be recruited to the outer mitochondrial membrane by associating with three different AKAPs to regulate mitochondrial dynamics, structure, mitochondrial respiration, trafficking, dendrite morphology, and neuronal survival. In this review, we survey the myriad of essential neuronal functions modulated by PKA but place a special emphasis on mitochondrially localized PKA. Finally, we offer an updated overview of how loss of PKA signaling contributes to the etiology of several brain degenerative diseases.
    No preview · Article · Jun 2015 · Reviews in the neurosciences
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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 ). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In neurons, enhanced PKA signaling elevates synaptic plasticity, promotes neuronal development, and increases dopamine synthesis. On the other hand, a decline in PKA signaling contributes to the etiology of several brain degenerative diseases including Alzheimer’s disease and Parkinson’s disease suggesting that PKA predominantly plays a neuroprotective role. A-kinase anchoring proteins (AKAP) are large multi-domain scaffold proteins that target PKA and other signaling molecules to distinct subcellular sites to strategically localize PKA signaling at dendrites, dendritic spines, cytosol, and axons. PKA can be recruited to the outer mitochondrial mitochondria membrane by associating with three three different AKAPs to regulate mitochondrial dynamics, structure, mitochondrial respiration, trafficking, dendrite morphology, and neuronal survival. In this review, we survey the myriad of essential neuronal functions modulated by PKA but place a special emphasis on mitochondrially-localized PKA. Finally, we offer an updated overview of how loss of PKA signaling contributes to the etiology of several brain degenerative diseases.
    Full-text · Article · Jan 2015 · Reviews in the neurosciences
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