Synthesis and characterization of a novel class of reducing agents that are highly neuroprotective for retinal ganglion cells.
ABSTRACT Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury, in part regulated by an intracellular superoxide anion burst, for which the target(s) are unknown. Shifting the RGC redox state towards reduction and preventing sulfhydryl oxidation is neuroprotective in vitro and in vivo, implying that one or more sulfhydryls on one or more critical proteins may be involved. We synthesized novel borane-protected analogues of the reductant tris(2-carboxyethyl)phosphine (TCEP) with the intent of increasing cell permeability and improving chemical stability, and tested their ability to increase RGC survival in vitro. Retinal ganglion cells of postnatal day 2-4 Long-Evans rats were retrogradely labeled with 4',6-diamidino-2-phenylindole (DAPI). At postnatal days 11-13 the animals were sacrificed, the retinas enzymatically dissociated and plated on poly-L-lysine-coated 96-well flat-bottomed tissue culture plates for 72 h in Neurobasal-A, B27 supplement lacking antioxidants, and TCEP, bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1), (3-propionic acid methyl ester)diphenylphosphine borane complex (PB2), or three commercially available phosphines. Viable DAPI-positive RGCs were identified by calcein-AM staining. At 72 h, PB1 was effective at rescuing acutely axotomized RGCs at concentrations from 1 nM to 100 microM. RGC survival with 1 nM PB1 was 174+/-12% of control (p=0.002). Another compound, PB2, rescued RGCs at 10 pM (177+/-24%; p=0.006) and 10 nM (251+/-34%; p=0.004) at 72 h. A PAMPA assay demonstrated that PB1 and PB2 were substantially more permeable than TCEP. These data demonstrate that modified reductants are effective RGC neuroprotectants at picomolar-nanomolar concentrations. We propose that these novel molecules may act by inhibiting the sulfhydryl oxidation effect of an intracellular superoxide burst.
Full-textDOI: · Available from: Christopher R Schlieve, May 01, 2014
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ABSTRACT: Glaucoma is the leading cause of irreversible blindness characterized by irremediable loss of retinal ganglion cells. Its risk increases with progressing age and elevated intraocular pressure. Studies have established that glaucoma is a neurodegenerative disorder in which the damage involves many brain tissues from retina to the lateral geniculate nucleus. Despite lot of research, complete pathomechanism of glaucoma is not known and there is no treatment available except modification of intraocular pressure pharmacologically and/or surgically. We here present a hypothesis inspired by studies across many areas of molecular and clinical sciences in an integrative manner that leads to a uniquely unconventional understanding of this disorder. Our hypothesis postulates that glaucoma may possibly be the diabetes of the brain. Based on the remarkable similarities between glaucoma and diabetes we propose glaucoma also to be a type of diabetes. Glaucoma and diabetes share many aspects from various molecular mechanisms to involvement of insulin and possible use of antidiabetics in glaucoma therapy. Additionally, Alzheimer's disease has already been proposed to be diabetes type-3. We show that Alzheimer's disease is cerebral glaucoma and diabetes at the same time which, by transitive property of similarities, again leads to our hypothesis that glaucoma is diabetes of the brain. Our proposition may lead to appreciation of certain important facets of glaucoma which have previously not been given due consideration. It also may lead to an alternative classification of diabetes as pancreatic and brain diabetes thereby widening the vision arena of the understanding of both these disorders.Medical Hypotheses 02/2014; 82(5). DOI:10.1016/j.mehy.2014.02.005 · 1.15 Impact Factor
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ABSTRACT: Glaucoma is a disease characterized by progressive optic nerve degeneration and is the leading cause of irreversible blindness worldwide. More than 60 million people globally are affected by glaucoma, of which 8 million people suffer from bilateral blindness, making glaucoma the second leading cause of bilateral blindness worldwide. Current management of glaucoma is aimed at reducing intraocular pressure via a number of different strategies. Current treatments do not attempt to correct the underlying pathology of glaucoma, which is the cell degeneration and ultimate death of retinal ganglion cells, thereby limiting their clinical efficacy. A neuroprotective approach to glaucoma management would address the underlying pathology and would, in theory, be beneficial to all patients regardless of risk and causative factors. Here it is proposed that leptin could be used as a potential neuroprotective agent in the management of glaucoma. Leptin has shown neuroprotective promise in a number of neurodegenerative diseases, and there has been increasing evidence that glaucomatous neurodegeneration is analogous to other neurodegenerative diseases in the central nervous system. Leptin could target retinal ganglion cell death by a number of mechanisms, namely apoptosis, oxidative stress and excitotoxicity reduction. This article presents evidence linking current understanding about leptin's neuroprotective effect and the molecular mechanisms underlying glaucoma.Medical Hypotheses 08/2013; 81(5). DOI:10.1016/j.mehy.2013.08.023 · 1.15 Impact Factor