PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP ⁺ in mesencephalic neurons and by MPTP in a mouse model of Parkinson's disease

Abstract

Many experimental data support the enhancement of neurotrophic factors as a means to modify neurodegeneration in Parkinson's disease. However, the translation of this to the clinic has proven problematic. This is likely due to the complex nature of the surgical gene delivery and cell-based approaches adopted to deliver proteinaceous neurotrophic factors to targets within the central nervous system. We investigated the ability of a novel, orally active, nonpeptide neurotrophic factor inducer, PYM50028 (Cogane), to restore dopaminergic function after 1-methyl-4-phenylpyridinium (MPP(+)) -induced damage to mesencephalic neurons in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned mice. In rat mesencephalic neurons, administration of PYM50028, either before or after MPP(+), significantly prevented and reversed both MPP(+)-induced neuronal atrophy and cell loss. These effects were potent and of a magnitude equivalent to those achieved by a combination of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). Oral administration of PYM50028 (10 mg/kg/day for 60 days) to MPTP-lesioned mice, commencing after a striatal impairment was evident, resulted in a significant elevation of striatal GDNF (297%) and BDNF (511%), and attenuated the loss of striatal dopaminergic transporter levels and dopaminergic neurons in the substantia nigra. PYM50028 did not inhibit monoamine oxidase B in vitro, nor did it alter brain levels of MPP(+) in vivo. PYM50028 has neuroprotective and neurorestorative potential and is in clinical development for the treatment of neurodegenerative disorders, including Parkinson's disease.

Driving GDNF expression: The green and the red traffic lights

“…Interestingly, it was suggested that XIB4035, a non-peptidyl small molecule that acts as a GDNF family receptor (GFR)a1 agonist and mimics the neurotrophic effects of GDNF in Neuro-2A cells, might have beneficial effects for the treatment of PD . More recently, the oral administration of PYM50028, a novel non-peptide neurotrophic factor inducer, to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice resulted in a significant elevation of striatal GDNF and attenuated the loss of dopaminergic neurons from the substantia nigra (Visanji et al, 2008).…”

Future Treatments for Parkinson's Disease: Surfing the PD Pipeline

“…Safinamide may be particularly useful if it is able to provide both an antiparkinsonian benefit and a reduction in dyskinesia. [52]. In MPTP-lesioned mice, oral administration of Cogane for 60 days reduced substantia nigra dopamine neuron loss, attenuated reduction of striatal dopamine transporter (DAT), and significantly increased striatal levels of BDNF (511%) and GDNF (297%) [52].…”

“…[52]. In MPTP-lesioned mice, oral administration of Cogane for 60 days reduced substantia nigra dopamine neuron loss, attenuated reduction of striatal dopamine transporter (DAT), and significantly increased striatal levels of BDNF (511%) and GDNF (297%) [52]. In MPTPlesioned parkinsonian monkeys, oral administration of Cogane for 18 weeks was associated with a 27% median reduction in parkinsonian disability at 9 weeks and a 43% reduction at 18 weeks [53].…”

GDNF and PD: Less Common Points of View

“…Zhang et al, 2008). Oral administration of smilagenin to MPTP-lesioned mice resulted in a significant elevation of striatal GDNF levels and attenuated the loss of dopaminergic neurons from the substantia nigra (Visanji et al, 2008). Interestingly, smilagenin is now undergoing phase I clinical testing (Aron & Klein, 2011).…”

“…Zhang et al, 2008). Oral administration of smilagenin to MPTP-lesioned mice elevates striatal GDNF levels and attenuates the loss of dopaminergic neurons (Visanji et al, 2008). Since smilagenin can be taken orally, readily crosses the blood-brain barrier, stimulates GDNF expression, and has neuroprotective effects in the MPTP mouse model of PD, hopefully it is a good candidate for the treatment of PD.…”