Retracted: Allopregnanolone restores the tyrosine hydroxylase‐positive neurons and motor performance in a 6‐OHDA‐injected mouse model

Abstract

Aims It has been reported that allopregnanolone (APα) promotes the neurogenesis of the neural progenitor cells (NPCs) in the subventricular zone (SVZ) and prevents the decrease of dopaminergic neurons in 6‐hydroxydopamine (6‐OHDA)‐treated mice by binding to γ‐aminobutyric acid A receptor (GABAAR) and then opening voltage‐gated L‐type Ca2+ channel, but the underlying mechanisms remain elusive. The aim of this study was to explore the possible involvement of GABAAR and calcium/calmodulin‐dependent protein kinase II delta 3 (CaMKIIδ3) in this process. Methods 6‐OHDA‐treated mice and primary cultured midbrain cells were administrated with APα and GABAAR antagonist bicuculline (Bic), and the proliferation and differentiation of NPCs, the tyrosine hydroxylase (TH)‐positive neurons and their fibers, the expression levels of CaMKIIδ3 and brain‐derived neurotrophic factor (BDNF), and motor functions were measured using ELISA, immunohistochemical staining, real‐time RT‐PCR, Western blot, and behavioral test. Results Allopregnanolone significantly promoted the phosphorylation of cytoplasmic CaMKIIδ3 and its nuclear translocation by binding to GABAAR, which, in turn, increased the expression levels of BDNF. This may account for the findings that the exogenous APα enhanced the proliferation and differentiation of NPCs, and ameliorated the nigrostriatal system and behavioral performance in 6‐OHDA‐treated mice. Conclusions Allopregnanolone may directly activate GABAAR, which, in turn, enhance the proliferation and differentiation of NPCs via upregulating the expression levels of CaMKIIδ3, and finally contribute to the restoration of dopaminergic neurons in 6‐OHDA‐treated mice.

Transcriptome profiling of five brain regions in a 6‐hydroxydopamine rat model of Parkinson’s disease

“…Moreover, some recent studies using the 6-OHDA rodent models have suggested several novel potential therapeutic targets for the restoration of dopaminergic neurons and the amelioration of behavior disorders in PD. For example, it has reported that GABAAR 43 and GluN2D 44 may be the potential candidates for PD, consistent with the results of changes in the dopaminergic, GABAergic, and glutamatergic synapses in this study. These findings demonstrate that PD is a comprehensive disease requiring multi-targets combined therapy, and finding the main sticking point is the key to select the therapeutic target.…”

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

“…The precise mechanism, by which allopregnanolone may have induced BDNF expression upregulation, is still elusive, but a recent investigation proposed that allopregnanolone binding at GABA A R leads to voltage-gated L-type Ca 2+ channel opening and subsequent phosphorylation of the calcium/calmodulin-dependent protein kinase II δ3 subunit (CaMKIIδ3), which then increases BDNF mRNA expression [ 69 ]. Further studies should determine potential transcription factors/regions for the BDNF gene that allopregnanolone could regulate directly or indirectly.…”

From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy

“…3α,5α-THPROG, a metabolite of progesterone, showed superior effects on pathophysiology, cognition, and memory in a 3xTg AD mouse model [177,178], and the underlying mechanism involved 3α,5α-THPROG regulating glucose metabolism, mitochondrial bioenergetics, and cholesterol homeostasis in the brain [179]. In contrast to the inconclusive results of progesterone treatment for PD [58], 3α,5α-THPROG showed better improved cognitive and motor functions in MPTPor 6-OHDA-induced PD mouse models [180,181].…”