Callithrix jacchus (common marmoset) is one of the more primitive non-human primate species and is used widely in fundamental biology, pharmacology and toxicology studies. Marmosets breed well in captivity with good reproductive efficiencies and their sexual maturity is reached within 18 months of age allowing for rapid expansion of colonies and early availability of sexually mature animals permitting an earlier assessment of product candidates in the adult. Their relatively small size allows a reduction in material requirements leading to a reduction in development time and cost. Fewer animals are also required due to their ability to be used in both pharmacology and toxicology (nonclinical) studies. These factors, alongside a better understanding of their optimal nutrient and welfare requirements over recent years, facilitate the generation of a more cohesive and robust dataset. With the growth of biotechnology-derived pharmaceuticals, non-human primate use has, by necessity, also increased; nevertheless, there is also a growing public call for minimizing their use. Utilizing, the more primitive marmoset species may provide the optimal compromise and once the scientific rationale has been carefully considered and their use justified, there are several advantages to using the marmoset as a model in nonclinical development of pharmaceutical products.

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.

No abstract

In comparison with a matched placebo, the consumption of HgPE for 15 d appeared to be associated with significant adverse changes in some vital signs and laboratory parameters. HgPE was less well tolerated than was the placebo and did not show any significant effects on energy intakes or body weights relative to the placebo. This trial was registered at clinicaltrials.gov as NCT01306422.

Tyrosine hydroxylase immunohistochemical analysis revealed that in cultured mesencephalic dopaminergic neurons smilagenin (SMI), added prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP + ), protected against the drop of neuron number and neurite outgrowth length caused by MPP + . Addition of anti-GDNF and/or anti-GFRa1 functional antibodies to the medium prior to SMI, eliminated mostly, though incompletely, the action of SMI. The expression of glial cell derived neurotrophic factor (GDNF) mRNA, but not GDNF receptor alpha1 (GFRa1) or receptor tyrosine kinase mRNA in MPP + intoxicated neurons was markedly elevated as early as 2 h after the addition of SMI with a peak at 24-48 h. Therefore, an important route of the protective action of SMI on dopaminergic neurons is to stimulate intrinsic GDNF expression.