Treatment of canine cognitive dysfunction with novel butyrylcholinesterase inhibitor

Canine cognitive dysfunction (CCD) is common in aged dogs and has many similarities with Alzheimer’s disease. Unfortunately, like Alzheimer’s disease, CCD cannot be cured. In the present study, we treated dogs with CCD with our newly developed and characterized butyrylcholinesterase inhibitor (BChEi). Seventeen dogs were randomized into two groups (treated with BChEi and untreated) and followed for 6 months at regular check-ups. The dogs’ cognitive status was determined by a Canine Dementia Scale (CADES) questionnaire and two cognitive tests. In dogs with moderate cognitive impairment, treatment caused significant improvement in the clinical rating of cognitive abilities and the performance-based tests of cognitive functioning when compared to the untreated group (p < 0.001). Dogs treated with BChEi showed markedly improved cognitive function with enhanced quality of life. No side effects were observed in the treated dogs with moderate cognitive impairment. According to the results of this preliminary study, there is an indication that novel BChEi may be a promising drug for the treatment of CCD in dogs and may be an interesting candidate for the treatment of Alzheimer's disease in humans. However, further clinical studies are needed to confirm this.

Treatment of Canine Cognitive Dysfunction With Novel Butyrylcholinesterase Inhibitor

Background: Canine cognitive dysfunction (CCD) is common in aged dogs and has many similarities with Alzheimer’s disease. Unfortunately, like Alzheimer’s disease, CCD cannot be cured. Methods: In the present study, we treated dogs with CCD with our newly developed and characterized butyrylcholinesterase inhibitor (BChEi). Seventeen dogs were randomized into two groups (treated with BChEi and untreated) and followed for 6 months at regular check-ups. The dogs’ cognitive status was determined by a CADES questionnaire and two cognitive tests. Results: In dogs with moderate cognitive impairment, treatment caused significant improvement in the clinical rating of cognitive abilities and the performance-based tests of cognitive functioning when compared to the untreated group (p < 0.001). Dogs treated with BChEi showed markedly improved cognitive function with enhanced quality of life. No side effects were observed in the treated dogs with moderate cognitive impairment. Conclusions: Novel BChE inhibitor is a promising candidate for treating CCD, and might be an interesting canidate drug for the treatment of Alzheimer disease in humans.

Discovery of a Selective 6-Hydroxy-1, 4-Diazepan-2-one Containing Butyrylcholinesterase Inhibitor by Virtual Screening and MM-GBSA Rescoring

Alzheimer disease (AD) is the most common form of dementia characterized by the loss of cognitive abilities through the death of central neuronal cells. In this study, structure-based virtual screens of 2 central nervous system-targeted libraries followed by molecular mechanics/generalized born surface area rescoring were performed to discover novel, selective butyrylcholinesterase (BChE) inhibitors, which are one of the most effective therapeutic strategies for the treatments in late-stage AD. Satisfyingly, compound 5 was identified as a highly selective low micromolar inhibitor of BChE (BChE IC50 = 1.4 μM). The binding mode prediction and kinetic analysis were performed to obtain detailed information about compound 5. Besides, a preliminary structure–activity relationship investigation of compound 5 was carried out for further development of the series. The present results provided a valuable chemical template with a novel scaffold for the development of selective BChE inhibitors.

Physostigmine: A Plant Alkaloid Isolated from Physostigma venenosum: A Review on Pharmacokinetics, Pharmacological and Toxicological Activities

Medicinal plants have been documented as an important source for discovering new pharmaceutical molecules that have been used to treat serious diseases. Strikingly, previous reports stated that natural products and their derived compounds exhibit lesser side effects and improved efficacy than other synthetic counterparts. Physostigmine, a parasympathomimetic plant alkaloid isolated from the West African perennial shrub Physostigma venenosum, it shows a narrow therapeutic index and a short life span, despite its ability to penetrate the blood-brain barrier (BBB). It is a widely known reversible butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) inhibitor and has been documented to treat various ailments such as Alzheimer’s disease. Pharmacologically, physostigmine was first reported as an antidote for atropine scopolamine and belladonna alkaloids toxicity. Recently, it has been documented as a therapy for treating several ailments including glaucoma, myasthenia gravis and the intoxication caused by tricyclic antidepressant overdoses, anti-histamines, antipsychotics, and benzodiazepines. Physostigmine has been reported to be absorbed from the gastrointestinal tract and showed short half-life, as, after the oral administration of 2 mg of physostigmine salicylate, the peak plasma concentration reached to 30 minutes. This review examines the biological activities, pharmacokinetics, and toxicity of physostigmine extracted from P. venenosum. Keywords: Physostigma venenosum, Physostigmine, pharmacological activities, acetylcholinesterase and butyrylcholinesterase inhibitor.