Reversal of dopamine neurons and locomotor ability degeneration in aged rats with smilagenin

• For the first time, smilagenin was shown to improve motor behavior in aged rats.
• Administration of smilagenin resulted in a significant dopaminergic neuroprotection.
• Smilagenin elevated GDNF levels in both the striatum and midbrain.

The purpose of this paper is to study the effect of smilagenin (SMI) (PYM50028), a sapogenin compound originally identified from Chinese medicinal herb, on dopamine neurons and locomotor ability in aged rats. Experiments were carried out on young and aged Sprague–Dawley rats, which were daily administered with either SMI (18 mg/kg/day) or vehicle (0.5% sodium carboxymethycellulose [CMCNa]). Open-field and rotarod performance tests revealed that behavioral ability was impaired in aged rats and was improved by oral administration of smilagenin. Immunohistochemical data showed that tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) were altered with aging and were increased by smilagenin treatment. Likewise, the dopamine receptor density and the striatal dopamine transporter (DAT) density (125I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane [125I-FP-CIT] autoradiography) were significantly lowered in aged rats as compared to young rats, and treatment with smilagenin significantly elevated the dopamine receptor and DAT density in aged rats. Furthermore, smilagenin enhances glial cell-derived neurotrophic factor (GDNF) release both in the striatum and midbrain. These results indicate a possible role of smilagenin in the treatment of age-related extrapyramidal disorders.