Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate...Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.展开更多
Alzheimer’s disease (AD) is a progressive neurological disorder primarily affecting new memory formation as well as retrieval of previously acquired memories. According to World Health Organization, current global po...Alzheimer’s disease (AD) is a progressive neurological disorder primarily affecting new memory formation as well as retrieval of previously acquired memories. According to World Health Organization, current global population suffering from cognitive impairment is estimated to 37 million. The number is projected to double in next one and half decade. Half of the population afflicted with dementia is represented by AD patients. Current therapies, which provide marginal symptomatic relief to AD patients, are effective only in half of the patient population. In depth understanding of the molecular mechanism of the disease is urgently required to develop more effective therapies. Therapies in clinical development may either offer symptomatic relief to patients or provide pure disease modifications, thus limiting benefit to patients. 5-HT4 receptor agonists offer an attractive option for the treatment of AD patients. Activation of 5- HT4 receptor under preclinical conditions is demonstrated to improve neurotransmission and enhance the release of acetylcholine resulting in the memory formation. In various cell based and animal models, partial 5-HT4 receptor agonists are demonstrated to promote the release of soluble amyloid precursor protein alpha and block the release of amyloid beta peptide offering suitable candidates as disease modification agents. Remarkably, 5-HT4 receptor agonists are also reported to induce neurogenesis in hippocampus as well as enteric system through the activation of cyclic AMP response element binding protein in rodents. Taken together, 5-HT4 agonists address all major facets of Alzheimer’s disease and may provide therapeutic potential for other neurological disorders.展开更多
文摘Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.
文摘Alzheimer’s disease (AD) is a progressive neurological disorder primarily affecting new memory formation as well as retrieval of previously acquired memories. According to World Health Organization, current global population suffering from cognitive impairment is estimated to 37 million. The number is projected to double in next one and half decade. Half of the population afflicted with dementia is represented by AD patients. Current therapies, which provide marginal symptomatic relief to AD patients, are effective only in half of the patient population. In depth understanding of the molecular mechanism of the disease is urgently required to develop more effective therapies. Therapies in clinical development may either offer symptomatic relief to patients or provide pure disease modifications, thus limiting benefit to patients. 5-HT4 receptor agonists offer an attractive option for the treatment of AD patients. Activation of 5- HT4 receptor under preclinical conditions is demonstrated to improve neurotransmission and enhance the release of acetylcholine resulting in the memory formation. In various cell based and animal models, partial 5-HT4 receptor agonists are demonstrated to promote the release of soluble amyloid precursor protein alpha and block the release of amyloid beta peptide offering suitable candidates as disease modification agents. Remarkably, 5-HT4 receptor agonists are also reported to induce neurogenesis in hippocampus as well as enteric system through the activation of cyclic AMP response element binding protein in rodents. Taken together, 5-HT4 agonists address all major facets of Alzheimer’s disease and may provide therapeutic potential for other neurological disorders.
