Effect of estrogen receptor agonists treatment in MPTP mice: evidence of neuroprotection by an ERα agonist

Abstract

Beneficial effects of 17β-estradiol (17β-E 2) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion are well documented but the mechanisms implicated are poorly understood. The present experiments investigated the effect of estrogen receptor (ER) agonists treatment in MPTP mice as compared to 17β-E 2. The agonists specific for each subtype were 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) tris-phenol (PPT) (ERα agonist), 2,3- bis(4-hydroxyphenyl)-propionitrile (DPN) and Δ3-diol (5-androsten-3β, 17β-diol, also known as 5-androstenediol, androstenediol or hermaphrodiol) (ERβ agonists). Biogenic amines were assayed by HPLC with electrochemical detection. 8 mg/kg of MPTP was administered to give a moderate depletion of striatal DA and its metabolite dihydroxyphenylacetic acid (DOPAC). Protection against MPTP-induced striatal DA and DOPAC depletion was obtained with PPT and 17β-E 2 but not with DPN or Δ3-diol. The striatal dopamine transporter (DAT) was assayed by autoradiography with [ 125I]RTI-121-specific binding. A positive and significant correlation was observed between striatal DA concentrations and [ 125I]RTI-121-specific binding, suggesting that estrogenic treatment that prevented the MPTP-induced DA depletion also prevented loss of DAT. The effect of PPT suggests the implication of an ERα in the estrogenic neuroprotection against MPTP. Pointing out which ER is implicated in neuroprotection becomes helpful in designing more specific estrogenic drugs for protection of the aging brain.