Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease

Soncrant, Timothy T.; Raffaele, Kathleen C.; Asthana, Sanjay; Berardi, Annamaria; Morris, Philip; Haxby, James V.

doi:10.1007/bf02244889

Cited by 68 publications

(35 citation statements)

References 39 publications

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“…Arecoline has been shown to bind to the M2 muscarinic receptors but not the nicotinic receptors [15]. A small clinical study showed that, when arecoline was given continually by intravenous infusion in AD patients, it enhanced verbal memory [16]. Derivatives of arecoline have been synthesized in order to improve selectivity for cortical muscarinic ACh receptors and two examples are Lu 25-109 and talsaclidine 8 which are M 1 receptor agonists.…”

Section: Ad: the Use Of Cholinergic Compoundssupporting

confidence: 43%

Natural Products and Derivatives Affecting Neurotransmission Relevant to Alzheimer’s and Parkinson’s Disease

2005

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The two major neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterised by low levels in the brain of the neurotransmitters acetylcholine (ACh) and dopamine (DA), respectively. Clinical treatment of these two conditions is palliative and relies, in most cases, on improving stimulation at the relevant receptors by either increasing levels of the endogenous neurotransmitter or by the use of substances which have a similar agonist response. Natural products continue to provide useful drugs in their own right but also provide templates for the development of other compounds. The major advances in the treatment of AD have been the use of acetylcholinesterase inhibitors such as galantamine, huperzine A, physostigmine and its derivatives to increase the levels of ACh rather than the use of cholinergic compounds, although compounds with nicotinic properties have attracted some interest. In contrast, the treatment of PD has relied on the elevation of DA levels by use of L-DOPA, its precursor, and by the administration of dopaminergic agonists, especially the ergot alkaloid derivatives. The use of inhibitors of enzymes that cause breakdown of DA is an avenue which is being explored. As well as the major natural products of clinical interest, the paper discusses the chemistry, activity and usage of the constituents of plants used in traditional medicine for the treatment of diseases presenting symptoms similar to those characteristic for Alzheimer’s or Parkinson’s disease.

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Section: Ad: the Use Of Cholinergic Compoundssupporting

confidence: 43%

Natural Products and Derivatives Affecting Neurotransmission Relevant to Alzheimer’s and Parkinson’s Disease

2005

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“…Bell-shaped efficacy curves in animal cognitive models have been noted with a number of mechanistically diverse procognitive agents [27][28][29][30][31][32] and in clinical studies as well. [33][34][35] This genre of dose-response relationship between neurochemistry and behavior suggests that a fine permissive tuning of cortical monoaminergic neurotransmission probably accounts for the expression of cognitive amelioration.…”

Section: Discussionmentioning

confidence: 40%

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine

et al. 2005

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Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.), -increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine a-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.) -currently the most commonly prescribed medication for the treatment of ADHD -and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

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“…Yes (Bartus and Dean 1988c) Yes (Kaye et al 1982;Summers et al 1981Summers et al , 1986 Muscarinic agonist (nonselective) Arecoline Yes (Bartus et al 1980a) Yes (Christie et al 1981;Raffaele et al 1991;Soncrant et al 1993) Muscarinic agonist (non-selective) Oxotremorine…”

Section: Attempts To Extend the Insight To Help Refine Rodent Modelsmentioning

confidence: 40%

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Bartus¹,

Dean

2008

Psychopharmacology

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Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.

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Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease

Cited by 68 publications

References 39 publications

Natural Products and Derivatives Affecting Neurotransmission Relevant to Alzheimer’s and Parkinson’s Disease

Natural Products and Derivatives Affecting Neurotransmission Relevant to Alzheimer’s and Parkinson’s Disease

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

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