Neuroprotective and neurotrophic effects of Lanthionine Ketimine Ester

Marangoni, Natalia; Kowal, Kathy; Deliu, Zanë; Hensley, Kenneth; Feinstein, Douglas L.

doi:10.1016/j.neulet.2017.11.018

Cited by 7 publications

(9 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Next, we evaluated the cytotoxicity of the identified compounds. Several studies indicate many methods can be used to evaluate the cytotoxicity, including primary neurons and neuroblastoma cells cultures ( Shipley et al, 2016 ; Marangoni et al, 2018 ; Peng et al, 2018 ). Unfortunately, primary neuron cultures are difficult to perform, since mature neurons do not undergo cell division.…”

Section: Resultsmentioning

confidence: 99%

Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

et al. 2018

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with multiple etiologies. Beta-amyloid (Aβ) self-aggregation and overexpression of class IIa histone deacetylases (HDACs) are strongly implicated with AD pathogenesis. In this study, a series of novel diarylheptanoid derivatives were designed, synthesized and evaluated for use as dual Aβ self-aggregation and class IIa HDAC inhibitors. Among these compounds, 4j, 5c, and 5e displayed effective inhibitions for Aβ self-aggregation, HDAC5 activity and HDAC7 activity with IC50 values of <10 μM. The compounds contain three common features: (1) a catechol or pyrogallol moiety, (2) a carbonyl linker and (3) an aromatic ring that can function as an HDAC cap and create hydrophobic interactions with Aβ1-42. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H2O2-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation.

show abstract

Section: Resultsmentioning

confidence: 99%

Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This suggests that beneficial actions of LKE in EAE may be mediated, at least in part, to increases in CRMP2 activity. Our findings that LKE exerts direct neuroprotective and neurotrophic effects (Marangoni et al., 2018) prompted us to develop a neuronal CRMP2 cKO mice to explore the roles of neuronal CRMP2 during EAE. In female mice with homozygous neuronal CRMP2 cKO, disease severity was reduced, while in males, although initial disease progression was slightly delayed, it eventually reached similar severity in WT and cKO mice.…”

Section: Discussionmentioning

confidence: 99%

“…LKE is neuroprotective in mouse models of ischemia (Nada et al., 2012), Alzheimer’s disease (AD) (Hensley et al., 2013; Koehler et al., 2018), fluid percussion injury (Hensley et al., 2016), and spinal cord injury (Kotaka et al., 2017). We reported that LKE has direct neuroprotective and neurotrophic effects on human neuroblastoma SH-SY5Y cells and on primary mouse cerebellar granule cells (Marangoni et al., 2018); and that in primary oligodendrocyte progenitor cells (OPCs) LKE induced branch elongation and increased messenger RNA (mRNA) levels of markers of OPC maturation (Savchenko et al., 2019). However, whether the beneficial actions of LKE in EAE are mediated via effects on neurons or other cell types is not yet known.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Conditional Knockout of Collapsin Response Mediator Protein 2 Ameliorates Disease Severity in a Mouse Model of Multiple Sclerosis

et al. 2019

Self Cite

View full text Add to dashboard Cite

We previously showed that treatment with lanthionine ketimine ethyl ester (LKE) reduced disease severity and axonal damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis and increased neuronal maturation and survival in vitro. A major target of LKE is collapsin response mediator protein 2 (CRMP2), suggesting this protein may mediate LKE actions. We now show that conditional knockout of CRMP2 from neurons using a CamK2a promoter to drive Cre recombinase expression reduces disease severity in the myelin oligodendrocyte glycoprotein (MOG) 35-55 EAE model, associated with decreased spinal cord axonal damage, and less glial activation in the cerebellum, but not the spinal cord. Immunohistochemical staining and quantitative polymerase chain reaction show CRMP2 depletion from descending motor neurons in the motor cortex, but not from spinal cord neurons, suggesting that the benefits of CRMP2 depletion on EAE may stem from effects on upper motor neurons. In addition, mice in which CRMP2 S522 phosphorylation was prevented by substitution for an alanine residue also showed reduced EAE severity. These results show that modification of CRMP2 expression and phosphorylation can influence the course of EAE and suggests that treatment with CRMP2 modulators such as LKE act in part by reducing CRMP2 S522 phosphorylation.

show abstract

“…This leads to the conclusion that LKE does not ameliorate OKA-induced neurodegeneration directly but rather through an indirect route. Several studies, including anecdotal evidence, show that LKE has the tendency to work better in systems under stress [33]. It is plausible, but needs to be further explored, that LKE has nootropic effects that act in a positive feedback loop when it is administered to a system that has been given an insult.…”

Section: Discussionmentioning

confidence: 99%

Lanthionine ketimine-5-ethyl ester provides neuroprotection in a zebrafish model of okadaic acid-induced Alzheimer's disease

Koehler

Shah

Hensley

et al. 2018

Neurochemistry International

Self Cite

View full text Add to dashboard Cite

Okadaic acid (OKA) is a protein phosphatase 2A inhibitor that is used to induce neurodegeneration and study disease states such as Alzheimer's disease (AD). Lanthionine ketimine-5-ethyl ester (LKE) is a bioavailable derivative of the naturally occurring brain sulfur metabolite, lanthionine ketimine (LK). In previously conducted studies, LKE exhibited neuroprotective and neurotrophic properties in murine models but its mechanism of action remains to be clarified. In this study, a recently established zebrafish OKA-induced AD model was utilized to further elucidate the neuroprotective and neurotrophic properties of LKE in the context of an AD-like condition. The fish were divided into 3 groups containing 8 fish per group. Group #1 = negative control, Group #2 = 100 nM OKA, Group #3 = 100 nM OKA +500 μM LKE. OKA caused severe cognitive impairments in the zebrafish, but concomitant treatment with LKE protected against cognitive impairments. Further, LKE significantly and substantially reduced the number of apoptotic brain cells, increased brain-derived neurotrophic factor (BDNF), and increased phospho-activation of the pro-survival factors pAkt (Ser 473) and pCREB (Ser133). These findings clarify the neuroprotective and neurotrophic effects of LKE by highlighting particular survival pathways that are bolstered by the experimental therapeutic LKE.

show abstract

Neuroprotective and neurotrophic effects of Lanthionine Ketimine Ester

Cited by 7 publications

References 31 publications

Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

Neuronal Conditional Knockout of Collapsin Response Mediator Protein 2 Ameliorates Disease Severity in a Mouse Model of Multiple Sclerosis

Lanthionine ketimine-5-ethyl ester provides neuroprotection in a zebrafish model of okadaic acid-induced Alzheimer's disease

Contact Info

Product

Resources

About