Treatment strategies for Alzheimer's disease

Bowen, David M.; Francis, Paul T.; Pangalos, Menelas N.; Stephens, P.H.; Procter, Andrew W.; Lewis, P A

doi:10.1016/0140-6736(92)91050-i

Cited by 40 publications

(11 citation statements)

References 5 publications

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“…In general, systemic 8-OH-DPAT may produce cognitive effects mediated by its action at the 5-HT1a receptor site that can be partialled out from its non-speci®c effects with appropriate procedures. In Alzheimer's disease the hypoactivity of cortical pyramidal neurones, produced by the hyperpolarizing effect of 5-HT and its agonists, can be reversed by treatment with 5-HT1a receptor antagonists (Bowen et al, 1992;Dijk et al, 1995;Francis et al, 1993). A more direct test of this hypothesis would require an animal model that uses lesions of the relevant cortico-cortical glutamate neurones .…”

Section: Discussionmentioning

confidence: 96%

Rapid visual learning in the rat: Effects at the 5-HT1a receptor subtype

Cassaday¹,

Simpson²,

Gaffan³

2000

The Quarterly Journal of Experimental Psychology B

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The 5-hydroxytryptamine1a (5-HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 96%

Rapid visual learning in the rat: Effects at the 5-HT1a receptor subtype

Cassaday¹,

Simpson²,

Gaffan³

2000

The Quarterly Journal of Experimental Psychology B

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“…Acetylcholine: In the past decade, treatment for AD has largely involved replacement of neurotransmitters that are known to be lacking in AD, mostly based on the cholinergic hypothesis of AD [203,298,299]. To improve cholinergic neurotransmission, different strategies have been investigated including the increase of ACh synthesis and presynaptic release, the stimulation of cholinergic postsynaptic muscarinic and nicotinic receptors, and the reduction of ACh synaptic degradation with cholinesterases inhibitors.…”

Section: Drugs Involved In Neurotransmission Improvementmentioning

confidence: 99%

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

Pereira¹,

Agostinho²,

Moreira³

et al. 2005

CDTCNSND

112

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The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Abeta neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Abeta cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Abeta and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Abeta species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

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“…Acetylcholinesterase (AChe) inhibitors have demonstrated efficacy in stabilizing executive functioning, cognitive abilities, and behavioral symptoms in some adults with Alzheimer’s or vascular dementia (12, 13). More recently, AChe inhibitors have shown promise in improving executive function, attention and memory in adults and children with Down syndrome or autism (14–16).…”

Section: Introductionmentioning

confidence: 99%

Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: A pilot study

Castellino

Tooze

Flowers

et al. 2012

Pediatric Blood & Cancer

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Background Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction. Procedure A single institution open-label pilot study was conducted in childhood BT survivors: ≥ 1 year from cancer treatment; and who received > 23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug. Results From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9–11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (p<=0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (p= 0.007), and the Number/Letter task (p= 0.018). Conclusions Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

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Treatment strategies for Alzheimer's disease

Cited by 40 publications

References 5 publications

Rapid visual learning in the rat: Effects at the 5-HT1a receptor subtype

Rapid visual learning in the rat: Effects at the 5-HT1a receptor subtype

Alzheimers Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies

Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: A pilot study

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