Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model

Kuo, Michael; Beckman, Joseph S.; Shaw, Christopher A.

doi:10.1016/j.nbd.2019.104495

Cited by 29 publications

(35 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that copper regulation is important to cellular function and that dysfunction often leads to disease, therapeutics targeting copper maintenance could be useful in treatment [ 3 , 9 ]. For instance, diacetylbis(N(4)-methylthiosemicarbazonato)-copper(II) (Cu(II)-ATSM) is currently used for imaging tumor hypoxia, but a recent discovery indicates that Cu(II)-ATSM could be a potential therapeutic agent in the treatment of ALS [ 109 ]. Potential future treatments will rely on our understanding of copper trafficking and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Copper Sources for Sod1 Activation

et al. 2020

View full text Add to dashboard Cite

Copper ions (i.e., copper) are a critical part of several cellular processes, but tight regulation of copper levels and trafficking are required to keep the cell protected from this highly reactive transition metal. Cu, Zn superoxide dismutase (Sod1) protects the cell from the accumulation of radical oxygen species by way of the redox cycling activity of copper in its catalytic center. Multiple posttranslational modification events, including copper incorporation, are reliant on the copper chaperone for Sod1 (Ccs). The high-affinity copper uptake protein (Ctr1) is the main entry point of copper into eukaryotic cells and can directly supply copper to Ccs along with other known intracellular chaperones and trafficking molecules. This review explores the routes of copper delivery that are utilized to activate Sod1 and the usefulness and necessity of each.

show abstract

Section: Discussionmentioning

confidence: 99%

Copper Sources for Sod1 Activation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Delivery of copper from Cu II (atsm) to cuproenzymes unsatiated for their natural copper requirement has been demonstrated in mutant SOD1 mice 3,5 . In these animals, the treatment also protects motor neurones in the CNS, mitigates associated deterioration of motor function, and improves overall survival [1][2][3][4][5][6][7] .…”

Section: Discussionmentioning

confidence: 99%

“…The orally bioavailable and blood-brain barrier penetrant copper compound diacetyl-bis(4-methylthiosemicarbazonato)copper II [Cu II (atsm)] is one of the most robustly tested and corroborated candidate drugs ever developed for the neurodegenerative condition of ALS, a fatal and rapidly progressive disease that selectively destroys motor neurones in the central nervous system (CNS). Pre-clinical studies involving mouse models of the disease show that oral treatment with Cu II (atsm) protects motor neurones in the spinal cord, mitigates the motor symptoms of neuronal decline, and extends survival [1][2][3][4][5][6][7] . These outcomes include mitigation of disease progression when the treatment commences after symptom onset 2 .…”

Section: Introductionmentioning

confidence: 99%

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Hilton

Kysenius

Liddell

et al. 2020

Preprint

View full text Add to dashboard Cite

Objective: The copper compound Cu II (atsm) is in phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) consistently and reproducibly ameliorates neurodegeneration in mutant SOD1 mouse models of ALS where its neuroprotective activity has been ascribed in part to improving availability of copper to essential cuproenzymes. However, SOD1 mutations cause only ~2% of ALS cases with most cases being of unknown aetiology. Therapeutic pertinence of Cu II (atsm) to sporadic ALS is therefore unclear. Methods:We assayed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper handling, and the activities of cuproenzymes. Results:The natural distribution of copper is disrupted in sporadic ALS. The ALS-affected tissue has a molecular signature consistent with an unsatiated requirement for copper and cuproenzyme activity is affected. Copper levels are decreased in the ventral grey matter, the primary anatomical site of neuronal loss in ALS.Interpretation: Mice expressing mutant SOD1 recapitulate salient features of ALS. The unsatiated requirement for copper that is evident in these mice is a biochemical target for Cu II (atsm). Evidences provided here for disrupted copper bioavailability in human cases of sporadic ALS indicate that a therapeutic mechanism for Cu II (atsm) involving copper bioavailability is pertinent to sporadic cases of ALS, and not just those involving mutant SOD1.

show abstract

“…Some ointments containing Cu(II) and Zn(II) glycinates, such as [Cu(Gly)] (HGly is glycine) (6), are recommended for skin conditions [13]. Moreover, [Cu(atsm)] (7) (H2atsm is diacetylbis(N-4-methylthiosemicarbazone) as a drug for amyotrophic lateral sclerosis (ALS) [14], [Cu(dmbpy)(acac)(OH2)]NO3 (dmbpy is 4,4-dimethyl-2,2′- (3) for iron deficiency anemia, chlorophyllin (4) for wounds odors elimination, radiation burns, inflammatory diseases and liver cancer prevention, SOD1 (5) for inflammatory diseases, diabetic complications, atherosclerosis, Alzheimer's disease, cancer and rheumatic arthritis, [Cu(Gly)] (6) for skin conditions, [Cu(atsm)] (7) for amyotrophic lateral sclerosis and [Cu(dmbpy)(acac)(OH 2 )]NO 3 (8) for cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, [Cu(atsm)] (7) (H 2 atsm is diacetylbis(N-4-methylthiosemicarbazone) as a drug for amyotrophic lateral sclerosis (ALS) [14], [Cu(dmbpy)(acac)(OH 2 )]NO 3 (dmbpy is 4,4-dimethyl-2,2 -bipyridine, Hacac is acetylacetone) (8) from the Casíopeinas ® family [15] as well as (4) combined with disulfiram (dsf) [16] as antitumor drugs are currently underway in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Improvement in the Pharmacological Profile of Copper Biological Active Complexes by Their Incorporation into Organic or Inorganic Matrix

2020

View full text Add to dashboard Cite

Every year, more Cu(II) complexes are proven to be biologically active species, but very few are developed as drugs or entered in clinical trials. This is due to their poor water solubility and lipophilicity, low stability as well as in vivo inactivation. The possibility to improve their pharmacological and/or oral administration profile by incorporation into inorganic or organic matrix was studied. Most of them are either physically encapsulated or conjugated to the matrix via a moiety able to coordinate Cu(II). As a result, a large variety of species were developed as delivery carriers. The organic carriers include liposomes, synthetic or natural polymers or dendrimers, while the inorganic ones are based on carbon nanotubes, hydrotalcite and silica. Some hybrid organic-inorganic materials based on alginate-carbonate, gold-PEG and magnetic mesoporous silica-Schiff base were also developed for this purpose.

show abstract

Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model

Cited by 29 publications

References 52 publications

Copper Sources for Sod1 Activation

Copper Sources for Sod1 Activation

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Improvement in the Pharmacological Profile of Copper Biological Active Complexes by Their Incorporation into Organic or Inorganic Matrix

Contact Info

Product

Resources

About

Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model

Cited by 29 publications

References 52 publications

Copper Sources for Sod1 Activation

Copper Sources for Sod1 Activation

Disrupted copper availability in sporadic ALS: Implications for CuII(atsm) as a treatment option

Improvement in the Pharmacological Profile of Copper Biological Active Complexes by Their Incorporation into Organic or Inorganic Matrix

Contact Info

Product

Resources

About

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option