Comparison of neuroprotective effects of dihydrotestosterone, 17ß-estradiol, and Pueraria mirifica herb extract on cognitive impairment in androgen deficient male rats.

This study investigated the neuroprotective effects of dihydrotestosterone (DHT), 17ß-estradiol (E2), and Pueraria mirifica herb extract (PME; an alternative source of natural estrogens) on the (i) learning and memory in androgen-deficient male rats, and on the hippocampus expression levels of (ii) mRNA of genes associated with synaptic transmission and structure, neurofibrillary tangles, and amyloid plaques, and (iii) total and phosphorylated tau proteins. The four-month-old male rats were sham-operated or orchidectomized (ODX). The ODX rats were divided into four groups, and orally treated for 2 months with either 1 mL/d of distilled water or 100 mg/kg/d of PME; or subcutaneously injected with 1 mg/kg/d of DHT or 80 µg/kg/d of E2. The impairment of spatial learning behavior and memory capacity in the ODX rats was prevented by DHT, E2, and PME. Recovery of the orchidectomy-induced deterioration of the synaptic plasticity in the hippocampus of rats was ranked as E2 ≥ PME > DHT. Both DHT and PME mitigated the increased Tau3 and Tau4 mRNA levels, and Tau-5 and P-Tau Ser396 protein levels more than E2 (DHT ≥ PME > E2). Only DHT tended to decrease App mRNA expression level. In conclusion, DHT showed a stronger efficacy for mitigation of the impaired spatial learning behavior and memory capacity in androgen-deficient male rats compared to E2 and PME, and their mechanisms of action are slightly different.

Chronological Molecular Changes in Neuronal Communication in Androgen-Deficient Rats.

We investigated the early onset of molecular changes in the hippocampus of orchidectomy (ODX)-induced androgen-deficient rats. Transcript levels of the genes associated with loss of synaptic plasticity (Bdnf, Syn, GluN1, α7-nAChR, and M1-mAChR), formation of neurofibrillary tangles (Tau4 and Tau3), and amyloid plaques (App, Adam10, and Bace1), in the hippocampus of rats at 0, 1, 3, 6, and 9 days after ODX (D0, D1, D3, D6 and D9, respectively) were determined. Primarily, the sudden loss of androgen, as confirmed by the decreased serum testosterone levels and accessory sex organ weights, induced a chronological reduction in Syn (at D1), and increase in GluN1 (at D3), α7-nAChR, and M1-mAChR (at D6) and a decrease in Bdnf (at D9) transcript levels. Tau4 and Tau3 mRNA levels were increased at D6 and D9, respectively. No changes in App, Adam10, and Bace1 mRNA levels were detected within the 9-day study period. To confirm those changes were caused by androgen deprivation and not increasing age, the mRNA expression levels of those genes in 9-day orchidectomized rats (ODX-D9) were compared with age-matched intact rats. All changes of mRNA expression levels of the ODX-D9 rats were aligned with the D9 rats, except for GluN1 that was decreased in the ODX-D9 rats. Moreover, the total and phosphorylated tau protein levels were increased in the ODX-D9 rats. These results denote that androgen deficiency induces the early onset of neurodegeneration, while the loss of synaptic plasticity together with the formation of neurofibrillary tangles could be used as markers for neurodegenerative prediction.