The effects of neurosteroid allopregnanolone on synaptic dysfunction in the hippocampus in experimental parkinsonism rats: An electrophysiological and molecular study

  • The dopaminergic system is a powerful candidate targeted for changes of synaptic plasticity in the hippocampus. Higher incidence of Parkinson’s disease (PD) in men than women indicates the influence of sex hormones on the PD development. Previous studies have shown that neurodegenerative diseases such as PD are related to the decline of Allopregnanolon (Allo), a metabolite of progesterone; it is also well known that learning and memory are influenced by oscillations in steroidal hormones.
  • Although abnormalities in hippocampal plasticity have been observed in the toxic models of PD, effects of Allo on hippocampal LTP and hippocampal synaptic protein levels, which play an important role in maintaining the integrity of neural connections, have never been analyzed thus far. Experimental groups subjected to the long-term potentiation (LTP) were studied in the CA1 area of the hippocampus. In addition, the levels of hippocampal postsynaptic density protein 95 (PSD-95), neurexin-1 (Nrxn1) and neuroligin (Nlgn) as synaptic molecular components were determined by immunoblotting.
  • Although dopamine denervation did not alter basal synaptic transmission and pair-pulse facilitation of field excitatory postsynaptic potentials (fEPSPs), the induction and maintenance of LTP were impaired in the CA1 region. In addition, the levels of PSD-95, Nrxn1 and Nlgn were significantly decreased in the hippocampus of 6-OHDA-treated animals. Such abnormalities in synaptic electrophysiological aspects and protein levels were abolished by the treatment with Allo.
  • These findings showed that partial dopamine depletion led to unusual synaptic plasticity in the CA1 as well as the decrease in synaptic proteins in the hippocampus. Our results demonstrated that Allo ameliorated these deficits and preserved pre- and post-synaptic proteins. Therefore, Allo may be an effective factor in maintaining synaptic integrity in the mesolimbic pathway.

Allopregnanolone suppresses glioblastoma survival through decreasing DPYSL3 and S100A11 expression

Allopregnanolone (allo) is a physiological regulator of neuronal activity that treats multiple neurological disorders. Allo penetrates the blood-brain barrier with very high efficiency, implying that allo can treat CNS-related diseases, including glioblastoma (GBM), which always recurs after standard therapy. Hence, this study aimed to determine whether allo has a therapeutic effect on GBM. We found that allo enhanced temozolomide (TMZ)-suppressed cell survival and proliferation of TMZ-resistant cells. In particular, allo enhanced TMZ-inhibited cell migration and TMZ-induced apoptosis.
Additionally, allo strongly induced DNA damage characterized by γH2Ax. Furthermore, quantitative proteomic analysis, iTRAQ, showed that allo significantly decreased the levels of DPYSL3, S100A11, and S100A4, reflecting the poor prognosis of patients with GBM confirmed by differential gene expression and survival analysis. Moreover, single-cell RNA-Seq revealed that S100A11, expressed in malignant cells, oligodendrocytes, and macrophages, was significantly associated with immune cell infiltration. Furthermore, overexpression of DPYSL3 or S100A11 prevented allo-induced cell death. In conclusion, allo suppresses GBM cell survival by decreasing DPYSL3/S100A11 expression and inducing DNA damage.

Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes

Background: We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration and differentiation, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer’s disease (AD) pathology in a mouse model of AD. To further investigate the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and biogenesis in rat hippocampal astrocytes.
Method: E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, cells were subject to morphological, biochemical, metabolic and transcriptomic characterization of their mitochondrial phenotypes.
Result: In primary hippocampal astrocytes, Allo significantly attenuates serum deprivation-induced bioenergetic deficits and oxidative stress by enhancing mitochondrial biogenesis and rebalancing mitochondrial dynamics. Allo treatment significantly enhances astrocytic mitochondrial biogenesis via Nrf1/Tfam signaling and reverses mitochondrial hyperfusion by elevating the ratio of mitochondrial fission protein Drp1 to the fusion protein Opa1. Functionally, Allo-induced improvement in bioenergetic function is coupled with reduced inflammasome activation in astrocytes.
Conclusion: Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits that emerge in early phases of AD, with mitochondria being a major effector

Allopregnanolone Improves Locomotor Activity and Arousal in the Aged CGG Knock-in Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome

  • Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients.
  • Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2′-deoxyuridine (BrdU) labeling to examine adult neurogenesis.
  • The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS.

Allopregnanolone

B2385-25 Biovision each 444 EUR

Allopregnanolone

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Allopregnanolone

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Allopregnanolone

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Allopregnanolone (BSA)

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  • 309.60 EUR
  • 1963.20 EUR
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  • 493.20 EUR
  • 100 ug
  • 10 ug
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  • 200 ug
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Allopregnanolone (OVA)

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  • 678.00 EUR
  • 309.60 EUR
  • 1963.20 EUR
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  • 100 ug
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Allopregnanolone Antibody

10041-05011 AssayPro 150 ug 260.4 EUR

Allopregnanolone (AP) ELISA

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Allopregnanolone ELISA Kit

E4346-100 Biovision each 1018.8 EUR

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Allopregnanolone (AP) Antibody

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  • 493.20 EUR
  • 159.60 EUR
  • 1362.00 EUR
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  • 376.80 EUR
  • 100 ug
  • 10 ug
  • 1 mg
  • 200 ug
  • 50 ug

Allopregnanolone (AP) Antibody

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  • 427.20 EUR
  • 1095.60 EUR
  • 560.40 EUR
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  • 100 ug
  • 1 mg
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Allopregnanolone (AP) CLIA Kit

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  • 9567.60 EUR
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Allopregnanolone (AP) ELISA Kit

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DLR-AP-Ge-48T DL Develop 48T 585.6 EUR

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EKU02257-48T Biomatik Corporation 48T 641.06 EUR

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Intravenous and Intramuscular Allopregnanolone for Early Treatment of Status Epilepticus: Pharmacokinetics, Pharmacodynamics, and Safety in Dogs

  • Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABAA receptors. We hypothesize that ALLO may be useful as first-line treatment for status epilepticus (SE). Our objectives were to 1) characterize ALLO pharmacokinetics-pharmacodynamics following intravenous (IV) and intramuscular (IM) administration and 2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 min or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours post-dose.
  • Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal Emax equation.
  • Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes following IM administration were not observed. Based on PK/PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC50, but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM.
  • The rapid onset of effect following IV infusion suggests that ALLO may be useful in the early treatment of SE. Significance Statement The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. We have proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus.

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