Ptychopetalum olacoides, a traditional Amazonian “nerve tonic”, possesses anticholinesterase activity

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Abstract

The cholinergic hypothesis of Alzheimer disease (AD) has provided the rationale for the current pharmacotherapy of this disease, in an attempt to downgrade the cognitive decline caused by cholinergic deficits. Nevertheless, the search for potent and long-acting acetylcholinesterase (AChE) inhibitors that exert minimal side effects to AD patients is still an ongoing effort. Amazonian communities use traditional remedies prepared with Ptychopetalum olacoides (PO, Olacaceae) roots for treating various central nervous system conditions, including those associated with aging. The fact that PO ethanol extract (POEE) has been found to facilitate memory retrieval in the step down procedure in young and aged mice prompt us to evaluate its effects on AChE activity in memory relevant brain areas. POEE significantly inhibited AChE activity in vitro in a dose- and time-dependent manner in rat frontal cortex, hippocampus and striatum; a significant inhibition was also found in these same brain areas of aged (14 months) mice after acute administration of POEE (100 mg/kg ip). We propose that such AChE inhibitory activity is a neurochemical correlate of a number of therapeutic properties traditionally claimed for P. olacoides, particularly those associated with cognition.

Introduction

Cognitive impairment during normal aging as well as in the Alzheimer's disease (AD) is thought to be associated to the degeneration of the basal forebrain cholinergic neurons. The aging rat is a well-established model of spontaneous brain cholinergic hypoactivity, useful to study the effects of drugs on the cholinergic transmission, as well as on age-associated cognitive impairment (Quirion et al., 1995). Accordingly, transgenic mice overexpressing human acetylcholinesterase (AChE) in brain neurons have cognitive deterioration, corroborating the role of this system in the modulation of spatial memory Andres et al., 1996, Beeri et al., 1995. In addition, brain cholinergic deficits, especially in the neocortex, amygdala and hippocampus are important neuropathologic findings in AD patients (Cummings and Back, 1998), usually accompanying abnormal components of the neuronal cytoskeleton, such as tangles and β-amyloid senile plaques (Vickers et al., 2000). The cholinergic hypothesis of Alzheimer disease (AD) has provided the rationale for the current pharmacotherapy of this disease, in an attempt to downgrade the cognitive decline caused by cholinergic deficits. Among the possible strategies for enhancing brain cholinergic activity, acetylcholinesterase inhibitors (AChEIs) have been the most extensively used for the symptomatic treatment of AD. Physostigmine and tacrine are the only AChEIs reasonably evaluated in AD patients, even though their use is limited by the short half-life and peripheral cholinergic side effects of physostigmine, and the dose-dependent hepatotoxicity of tacrine Nordberg and Svensson, 1998, Watkins et al., 1994, Yoshida and Suzuki, 1993. While newer AChE inhibitors, such as donepezil and huperazine, have been recently introduced in the European market Rogers and Friedhoff, 1996, Sugimoto et al., 1992, the identification of a potent long-acting AChE inhibitor with fewer side effects in AD patients would be highly advantageous.

Brazil houses an enormous biological and cultural diversity, with several medicinal plants identified by local peoples as being useful for treating CNS disorders. Within the context of drug development, the interest in traditional medical systems has been mostly focused on its plant-based remedies, with the underlying understanding that some species may contain therapeutically useful compounds Abelson, 1990, Cragg and Newman, 2001. Ptychopetalum olacoides Bentham (PO, Olacaceae), known as “Marapuama” (and/or Muirapuama and Mirantã among others) is widely consumed throughout the Amazon region. Local communities use PO-based alcoholic infusions for the treatment of CNS-related ailments and/or during highly stressful periods Elisabetsky, 1987, Grenand et al., 1987, Siqueira et al., 1998, Steinmetz, 1962. The frequencies of elders amongst users, and by patients recovering from conditions associated with damage to the central nervous system (such as stroke), are of particular interest (Elisabetsky and Siqueira, 1998). It is noteworthy that PO has nowadays been included in dozens of herbal drugs or multivitamin dietary supplements at the international market, based on claims of enhanced physical and cognitive performance.

Recognizing the value of traditional knowledge, and the various CNS activities identified with an ethanol extract obtained from PO roots Siqueira et al., 1998, da Silva et al., 2002a, including the enhancement of memory retrieval in young and aged mice (da Silva et al., 2002b), the purpose of this study was to evaluate the effects of POEE on AChE activity.

Section snippets

Plant material

Roots of P. olacoides Bentham (PO, Olacaceae) were collected at the State of Pará (Brazil), and identified by Mr. Nelson Rosa (voucher deposited at the Goeldi Museum herbarium, MG 108036).

The plant species was further authenticated through quantitative analysis for lupeol in the roots using the method described by Auterhoff and Momberger (1971); we found an average lupeol yield of 0.28% in the roots, in accordance with the data published by these authors for this species.

Ethanol extract

The extractive

Results

No significant differences in AChE activity (dA/min) were found with phosphate buffer (data not shown) or DMSO over time; the absolute mean(±S.D.) dA/min for DMSO control groups were 0.0050(0.0011), 0.0054(0.0003) and 0.0056(0.0006) for frontal cortex, 0.0040(0.0005), 0.0039(0.0006) and 0.0041(0.0003) for hippocampus, and 0.0047(0.0004), 0.0049(0.0004) and 0.0051(0.0005) for striatum at 15, 30 and 60 min, respectively.

POEE significantly inhibited in vitro AChE activity, in a dose- and

Discussion

It is now widely accepted that hypoactivity of the cholinergic system plays a central role in cognitive deficits De Lacalle et al., 1996, Quirion et al., 1995, Taylor and Griffith, 1993. Accordingly, despite serious limitations in both efficacy and adverse effects, inhibition of AChE is the current basis for drug therapy in AD Rogers and Friedhoff, 1996, Sugimoto et al., 1992, Watkins et al., 1994.

We have recently found that P. olacoides ethanol extract (POEE) improved long-term memory

Acknowledgements

We gratefully acknowledge financial support received from FINEP/PRONEX, FAPERGS, CAPES, CNPq and PROPESQ-UFRGS. There is a patent request (PI0205432-9, INPI, Brazil) associated with this study.

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