Regulation of phase I and phase II neurosteroid enzymes in the hippocampus of an Alzheimer's disease rat model: A focus on sulphotransferases and UDP-glucuronosyltransferases.

Neurosteroids have been associated with neurodegenerative diseases because they are involved in the modulation of neurotransmitter, neurotropic and neuroprotective actions. Emerging evidence suggests that the enzymes responsible for the synthesis of neurosteroids change during the progression of Alzheimer's disease (AD). The present study aimed to assess the changes in phase I and II enzymes involved in the metabolism of neurosteroids of the progestogen, androgenic and estrogenic steroidogenic pathways and the possibility that the neurosteroids are actively converted into the most abundant metabolites (i.e. glucuronides and sulphates). The gene expression for the phase I and II neurosteroid biosynthetic enzymes were studied in the hippocampus of streptozotocin AD rat model. Male Sprague-Dawley rats were randomly divided into control, sham (saline injected into the hippocampus) and 3 and 12 weeks post-STZ administration (STZ-G3w and STZ-G12w, respectively) groups. Behavioral assessments showed memory impairment in both STZ-injected groups, whereas the formation of amyloid-beta was more pronounced in the STZ-12w group. Gene expression of the hippocampus revealed that glucuronidation and sulphation enzymes transcript of the phase I metabolites were upregulated at the late stage of the disease progression (Hsd17b10, Hsd3b1, Akr1c3 and Cyp19a1) except for Sts. The phase II Sult and Ugt enzymes were mostly upregulated in the STZ-G12w rats (Sult1a1, Sult1e1, Ugt1a1, Ugt1a7c, Ugt1a6, Ugt2b35 and Ugt2b17) and normally expressed in the STZ-G3w group (Sult2a2, Sult2a6, Sult2b1, Ugt2b7, Sult4a1 and Ugt1a7c). In conclusion, changes occur in the phase I and II enzymes transcript of the progestogen, androgenic and estrogenic steroidogenic pathways during the progression of AD.