PDE-4 inhibitor and selective GABA-A receptor modulator
Etazolate hydrochloride is a PDE-4 inhibitor and selective GABA-A receptor modulator [3].
PDE-4 modulates the release of inflammatory mediators through cAMP-dependent and -independent mechanisms. Selective targeting PDE-4 is a novel therapeutic approach in the treatment of inflammation-associated respiratory diseases, such as asthma and COPD (chronic obstructive pulmonary disease) [1].
In rat neuronal cortical cells, etazolate hydrochloride (0.2 μM) induced sAPPα through the stimulation of the α-secretase pathway, and exerted a neuroprotective effect against Aβ which was associated with sAPPα induction via the GABA-A receptor [2].
In 159 Alzheimer’s Disease patients, etazolate hydrochloride in combination with one AchEI (acetycholinesterase inhibitor) was shown to be safe and generally well tolerated in the Phase IIA study over a 3-month treatment period [3].
参考文献:
[1] Dastidar S G, Rajagopal D, Ray A.? Therapeutic benefit of PDE4 inhibitors in inflammatory diseases.[J]. Current Opinion in Investigational Drugs, 2007, 8(5):364-72.
[2] Marcade M, Bourdin J, Loiseau N, et al.? Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing.[J]. Journal of Neurochemistry, 2008, 106(1):392-404.
[3] Vellas B; Sol O; Snyder PJ; Ousset PJ; Haddad R; Maurin M; Lemarié JC; Désiré L; Pando MP; EHT0202/002 study group.? EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.[J]. Current Alzheimer Research, 2011, 8(2):203-12.
| Cell experiment [1]: | |
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Cell lines |
Neuronal cortical cells from Wistar rat embryos |
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Preparation method |
The solubility of this compound in sterile water is 50 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
48 h, 0~2 μM |
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Applications |
In cortical neurons, 0~2 μM etazolate hydrochloride dose-dependently increased secreted levels of non-amyloidogenic sAPPα. etazolate hydrochloride (0.2 μM) prevented the neurotoxicity of Aβ on cortical neurons via the GABA-A receptor, which was associated with α-secretase activity and sAPPα induction. Etazolate hydrochloride induced sAPPα through the stimulation of the α-secretase pathway, and didn’t affect the amyloidogenic pathway. |
| Clinical experiment [2]: | |
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Clinical models |
Alzheimer’s disease patients |
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Dosage form |
40 and 80 mg bid for 3 month, oral administration |
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Application |
Etazolate hydrochloride in combination with one AChEI ( acetycholinesterase inhibitor) was shown to be safe and generally well tolerated in this Phase IIA study in 159 Alzheimer’s Disease patients over a 3-month treatment period. Most of psychiatric and neurologic AEs (Adverse events) were observed in the high-dose (etazolate 80 mg bid) group, suggesting a potential dose-related effect. Gastrointestinal and cardiovascular related AEs were no more frequent in the etazolate groups compared to placebo, indicating the absence of a potential clinical adverse interaction between the AChEI and etazolate hydrochloride. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] Marcade M, Bourdin J, Loiseau N, et al. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing.[J]. Journal of Neurochemistry, 2008, 106(1):392-404. [2] Vellas B; Sol O; Snyder PJ; Ousset PJ; Haddad R; Maurin M; Lemarié JC; Désiré L; Pando MP; EHT0202/002 study group. EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.[J]. Current Alzheimer Research, 2011, 8(2):203-12. | |
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