Elsevier

European Journal of Pharmacology

Volume 745, 15 December 2014, Pages 84-90
European Journal of Pharmacology

Neuropharmacology and analgesia
Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice

https://doi.org/10.1016/j.ejphar.2014.10.026Get rights and content

Abstract

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

Introduction

Cognitive enhancers have received much attention in contemporary neuropharmacological research. Phosphodiesterase (PDE) inhibitors may work as cognitive enhancers due to their expression of phosphodiesterases in the central nervous system (CNS) (Menniti et al., 2006). Tadalafil (CAS number 171596-29-5) is a potential phosphodiesterase 5 (PDE-5) inhibitor (Schiefer and Sparing, 2005), which has been used to treat erectile dysfunction (Donatucci et al., 2008, Porst et al., 2009). It can cross the blood brain barrier (Garcia-Barroso et al., 2013). The association of cognitive disorders with PDE-1,4,5,8,9, and 10 inhibitors has been demonstrated previously (Schmidt, 2010, Zhang, 2010) where PDE-5 and 9 were found to be a common cognitive enhancer.

Tadalafil has been reported to improve cognitive function in a mouse model of Alzheimer׳s disease (Garcia-Barroso et al., 2013, Zhang et al., 2013). It reduces anxiety (Liebenberg et al., 2012) and memory impairment, and improves depressive disorder (Baek et al., 2011). Tadalafil reduces the immobility time in forced swim test in rodent model and stops maternal separation induced apoptosis in the hippocampus (Baek et al., 2011).

Dentate gyrus of hippocampus is a special brain area where neurogenesis occurs (Gould et al., 1997). This neurogeneration is associated with the learning and memory processes (Deng et al., 2010, Gould et al., 1997, Kempermann et al., 1997). However, stress factors reduce the formation of granule cells in the dentate gyrus (Tanapat et al., 1998). In addition, age related oxidative stress causes memory deficits in older individuals. Oxidative stress also affects synaptic plasticity in neural networks in the hippocampus (Haxaire et al., 2012). Previous study only report that tadalafil improves memory impairment by reducing apoptotic neuronal cell death (Baek et al., 2011) and ischemia-induced apoptotic neuronal cell death (Ko et al., 2009). But the effect of tadalafil on age related cognitive deficits has not been elucidated.

We aimed to investigate the effect of tadalafil on age related memory performance, locomotor activity, and oxidative stress in the hippocampus. Hippocampus plays a critical role in memory formation that is generally affected during the aging process. Oxidative stress is a major player in declining cognitive function that is influenced by the aging process. Tadalafil might have protective properties in the hippocampus as well as in relieving age-related cognitive decline.

Elderly people mostly suffer from erectile dysfunction and PDE-5 inhibitor such as tadalafil is mostly consumed by them. Elderly people also suffer age-related cognitive dysfunction. Young mice fight against the aging differently than the elderly at the molecular, structural, functional and cognitive levels (Villeda et al., 2014). Elderly mice are less capable to counteract oxidative stress in comparison to the young mice (Villeda et al., 2014). The pharmacological agents such as tadalafil could bring different results in these age groups since other PDE-5 inhibitor (sildenafil) showed vital role in age-related cognitive dysfunction in mouse model of aging (Palmeri et al., 2013).

The availability of PDE enzymes in the CNS open a new window to investigate the effect of PDE inhibitors in enhancing cognitive function. Recently it is reported that NO-cGMP plays a vital role in improving learning and memory functions (Jin et al., 2014). The lingering of cGMP action in the CNS may facilitate memory function. Therefore, we aimed to investigate the age-related protective effect of tadalafil in hippocampus.

Section snippets

Animal

Swiss-Albino male mice (Mus musculus) (30–35 g) were used in this study. They were housed in room temperature (25 °C) and adequate lighting condition with standard mice pellets and water. Mice were randomly divided into 4 groups. Control groups were treated with distilled water while test groups were treated with tadalafil (0.05 mg/kg) for 4 weeks. All experimental procedures were approved by the local ethical committee of North South University for animal experiments according to governmental

Radial arm maze

A one-way between subjects ANOVA was conducted to compare the effect of tadalafil on short term error for memory in young and old groups in tadalafil and placebo conditions. There was a significant effect of short term error on tadalafil at the P<0.05 level for the four conditions, F(3,31)=13.35, P=0.0001. Newman–Keuls multiple comparisons test showed that aged mice treated by tadalafil (M=4.55, S.D.=1.4) produced significantly less number of errors than their corresponding aged match control (M

Discussion

The result of the present study demonstrated that treatment with tadalafil improves memory function and reduces oxidative stress in both young and aged mice. RAM data indicates that tadalafil treated aged mice produced less number of short term and total errors than tadalafil treated young mice. Hippocampus is a vital part of the brain for memory formation. Hippocampus is involved in information processing regarding space due to the presence of place and grid cells. The effect of tadalafil on

Conclusion

In conclusion, we demonstrated that tadalafil improves working memory performance in aged mice and this improvement may be associated with the reduction of lipid peroxidation (MDA level) and increased catalase activity and cGMP level in the hippocampus. The result of the present study could be useful in the development of pharmacological strategy in combating the cognitive decline of the aging process.

Acknowledgments

We would like to acknowledge the contribution of Master thesis students at North South University, Dhaka, Bangladesh. We would like to give them special thanks for organizing necessary reagents in time during this study.

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