Development of novel small molecules for the treatment of ALS

Mathew, Biji; Ruiz, Pedro; Pathak, Vibha; Suto, Mark J.

doi:10.1016/j.bmcl.2020.126950

Cited by 8 publications

(6 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Meanwhile, the expression of non-canonical Wnt ligand Wnt5a is also abnormal in ALS mice [40,41]. In the current study, it was con rmed that canonical Wnt signaling pathway can be activated in the pathogenesis of ALS [4]. Furthermore, it was found that Wnt1, a canonical Wnt signaling molecule, can promote the proliferation and viability of SOD1 mutant NSC-34 cells, inhibit cell apoptosis and protect MNs.…”

Section: Discussionmentioning

confidence: 50%

See 1 more Smart Citation

Wnt5a Protects Motor Neuron in Amyotrophic Lateral Sclerosis by Regulating Wnt/Ca2+ Signaling Pathway

Liu

Zhou

Guan

et al. 2021

Preprint

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that lead to the degeneration and death of motor neurons (MNs). Wnt signaling participates in multiple neurodegenerative processes. Wnt5a is a critical signaling molecule in Wnt signaling pathway. Intracellular Ca2+ homeostasis is disrupted in a number of neurodegenerative diseases, and Ca2+/Calmodulin dependent protein kinase II (CaMKII) involved in various diseases associated with Ca2+ signaling abnormalities. Here, we found that Wnt5a modulated MNs degeneration during ALS. CaMKII is a key effector of signals derived from Wnt/Ca2+ signaling pathway. Its main subtypes CaMKII-α and CaMKII-β were down-regulated in the spinal cord of SOD1G93A transgenic mice (ALS mice) and SOD1 mutant motor neuron like hybrid (NSC-34) cells. In addition, results showed that CaMKII-α and CaMKII-β were positively regulated by Wnt5a in vitro. Using specific CaMKII inhibitor and activator, we found that Wnt5a promoted NSC-34 cells viability and proliferation, inhibited cells apoptosis and promoted cells neurite outgrowth via the Wnt/Ca2+ signaling pathway. These results indicate that Wnt5a confers neuroprotection by promoting neuronal proliferation, inhibiting cell apoptosis and promoting neurite growth through Wnt/Ca2+ signaling pathway. Therefore, targeting Wnt5a can be an effective strategy to treat ALS.

show abstract

Section: Discussionmentioning

confidence: 50%

“…ALS cases can be divided into sporadic ALS (SALS) and familial ALS (fALS). The former, which occurs randomly without a family history, represents about 90% of ALS cases, while the latter accounts for about 10% of ALS cases [4]. To date, more than 25 mutated genes have been pro led in SALS and fALS.…”

Section: Introductionmentioning

confidence: 99%

Wnt5a Protects Motor Neuron in Amyotrophic Lateral Sclerosis by Regulating Wnt/Ca2+ Signaling Pathway

Liu

Zhou

Guan

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, downregulation of KCC2 in spinal cord motor neurons is involved in spasticity associated with spinal cord injury [ 75 ], and CLP257 and 290, which increase the expression of KCC2, are candidate therapeutic agents [ 6 , 76 ]. Further, SOD1 , C9orf72 , and SMN1 have been identified as causative genes for amyotrophic lateral sclerosis and spinal muscular atrophy, in which the viability of spinal motor neurons is decreased [ 5 , 77 ], and treatment strategies targeting these genes are under development [ 78 , 79 , 80 ]. In addition, upregulation of NKCC1 in DRG neurons is involved in chronic pain, and bumetanide and furosemide suppress this upregulation, contributing to pain relief [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Retrograde Axonal Transport of Liposomes from Peripheral Tissue to Spinal Cord and DRGs by Optimized Phospholipid and CTB Modification

Fukui

Tateno

Nakamura

et al. 2022

IJMS

View full text Add to dashboard Cite

Despite recent advancements in therapeutic options for disorders of the central nervous system (CNS), the lack of an efficient drug-delivery system (DDS) hampers their clinical application. We hypothesized that liposomes could be optimized for retrograde transport in axons as a DDS from peripheral tissues to the spinal cord and dorsal root ganglia (DRGs). Three types of liposomes consisting of DSPC, DSPC/POPC, or POPC in combination with cholesterol (Chol) and polyethylene glycol (PEG) lipid were administered to sciatic nerves or the tibialis anterior muscle of mature rats. Liposomes in cell bodies were detected with infrared fluorescence of DiD conjugated to liposomes. Three days later, all nerve-administered liposomes were retrogradely transported to the spinal cord and DRGs, whereas only muscle-administered liposomes consisting of DSPC reached the spinal cord and DRGs. Modification with Cholera toxin B subunit improved the transport efficiency of liposomes to the spinal cord and DRGs from 4.5% to 17.3% and from 3.9% to 14.3% via nerve administration, and from 2.6% to 4.8% and from 2.3% to 4.1% via muscle administration, respectively. Modification with octa-arginine (R8) improved the transport efficiency via nerve administration but abolished the transport capability via muscle administration. These findings provide the initial data for the development of a novel DDS targeting the spinal cord and DRGs via peripheral administration.

show abstract

“…Several derivatives exhibited two-to-fivefold better activity compared to 88 but none of them had rat and human microsomal stability. 119…”

Section: Induction Of Sod2 Through Activation Of Nuclear Factor Kappa...mentioning

confidence: 99%

“…The α,β‐ unsaturated compound 88 , which increased NF‐κB expression and activation, upregulated SOD2 levels in vitro, and had activity in vivo in the hSOD1 G93A reference model of ALS, was selected for further optimization to identify more potent activators of NF‐κB. Several derivatives exhibited two‐to‐fivefold better activity compared to 88 but none of them had rat and human microsomal stability 119 …”

Section: Mutations In the Sod1 Genementioning

confidence: 99%

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Elmansy

Reidl

Rahaman

et al. 2023

Medicinal Research Reviews

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP‐43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.

show abstract

Development of novel small molecules for the treatment of ALS

Cited by 8 publications

References 29 publications

Wnt5a Protects Motor Neuron in Amyotrophic Lateral Sclerosis by Regulating Wnt/Ca2+ Signaling Pathway

Wnt5a Protects Motor Neuron in Amyotrophic Lateral Sclerosis by Regulating Wnt/Ca2+ Signaling Pathway

Retrograde Axonal Transport of Liposomes from Peripheral Tissue to Spinal Cord and DRGs by Optimized Phospholipid and CTB Modification

Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Contact Info

Product

Resources

About