Cholinergic hypofunction is one of the main causes of dementia and cognitive deficits in Alzheimer’s Disease (AD). Animal models that induced a long-term cholinergic hypofunction would be useful as a system for evaluating new cholinergic therapeutics. Drugs that can reverse or ameliorate memory impairments in testing rodents are potentially useful for the palliative treatment of AD....[ Read more ]

Cholinergic hypofunction is one of the main causes of dementia and cognitive deficits in Alzheimer’s Disease (AD). Animal models that induced a long-term cholinergic hypofunction would be useful as a system for evaluating new cholinergic therapeutics. Drugs that can reverse or ameliorate memory impairments in testing rodents are potentially useful for the palliative treatment of AD.

In this thesis, neurochemical and neuropharmacological effects of bis(12)-huperin have been studied for its specificity, potency and selectivity in in vitro and in vivo assays. The cholinergic hypothesis was employed as the basis of our research on the palliative treatment of AD.

Using neurochemical approach, inhibitory effects of bis(12)-huperin on acetylcholinesterase and butyrlcholinesterase, inhibition mechanisms of acetylcholinesterase, reversibility of acetylcholinesterase inhibition, inhibition on acetylcholinesterase after acute medication and time course of change in cholinesterase activity after oral administration were characterized. Using neuropharmacological approach, the potency of bis(12)-huperin was evaluated by examines its ability to reverse scopolamine, AF64A or Aβ-induced spatial memory impairments in rats using the Morris water maze. In addition, the ability to reverse bis(12)-huperin scopolamine-induced memory impairment was evaluated using partially baited radial arm maze task.

The results indicated that bis(12)-huperin could reversibly inhibit rat brain AChE in a non-competitive manner. Acute administration of bis(12)-huperin at 45 μmol/kg produced significant AChE inhibition at cortex, hippocampus, and striatum in rats with the effect being lasted for 2 hours. Furthermore, bis(12)-huperin could reverse scopolamine, AF64A or Aβ (1- 40)-induced spatial memory impairment in rats as assessed by the Morris water maze test as well as the scopolamine-induced spatial deficit model as assessed in partially baited radial arms maze test. The ensemble of evidence to support bis(12)-huperin be a novel and potential promising candidate for the palliative treatment of AD.