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Bisperoxovanadium promotes motor neuron survival in models of amyotrophic lateral sclerosis
Author(s) -
Tierney Lydia,
Wang Junmei,
Mann Ranjeet,
Lonsway Thomas,
Walker Chandler
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03929
Subject(s) - amyotrophic lateral sclerosis , motor neuron , pten , protein kinase b , neuroprotection , pi3k/akt/mtor pathway , neuroinflammation , tensin , excitotoxicity , spinal cord , biology , cancer research , programmed cell death , sod1 , microbiology and biotechnology , medicine , signal transduction , pathology , immunology , neuroscience , apoptosis , biochemistry , inflammation , disease
The objective of our study was to test the therapeutic efficacy of a small molecule, bisperoxovanadium (bpV), in cell culture and animal models of the motor neuron (MN) disease, amyotrophic lateral sclerosis (ALS). A common cause of hereditary ALS, a mutation in the superoxide dismutase 1 protein (mSOD1 G93A ), is well studied and available models recapitulate human disease progression and MN loss. BpV is a known inhibitor of the phosphatase and tensin homolog, PTEN, and we have shown that bpV promotes MN survival in traumatic nervous system injury models. PTEN is well known as a negative regulator of phosphatidylinositol‐3‐kinase (PI3K)/Akt signaling, and this signaling pathway is linked to bpV's neuroprotective effects. We hypothesized that bpV treatment of both a mSOD1 G93A MN cell line and mouse model ofALS would prevent MN degeneration and death. To test this hypothesis, we administered 400 μg/kg bpV intraperitoneally daily to mSOD1 G93A mice between 70 and 90 days of age, which is a period of lumbar spinal cord MN death in these mice. After treatment, we collected tissue and examined immunolabeling of MNs in cryosections of the lumbar spinal cord and microglial reactivity, which can contribute to neuroinflammation and exacerbate MN loss. For our in vitro model, we cultured motor neuron‐like NSC‐34 cells transfected with a plasmid to overexpress mutant SOD1 G93A , differentiated these cells for four days, and starved them in a serum‐free medium for 24 hours both with and without bpV. Furthermore, we administered an inhibitor of PI3K/Akt signaling, LY294002, in the cell culture model to determine bpV's influence on PTEN and elucidate a potential mechanism of its action. We found that 20 days of bpV therapy significantly reduced lumbar ventral horn MN loss ( p <0.05) but did not significantly influence microglial reactivity in mSOD1 G93A mice. BpV improved neuron viability in vitro , and PI3K/Akt signaling inhibition reversed this effect (both p <0.05). In conclusion, our study indicates that bpV treatment could be a useful neuroprotective therapy for ALS.