Elsevier

Biomedicine & Pharmacotherapy

Volume 96, December 2017, Pages 736-741
Biomedicine & Pharmacotherapy

Original article
Sodium valproate enhances doxorubicin-induced cognitive dysfunction in Wistar rats

https://doi.org/10.1016/j.biopha.2017.09.150Get rights and content

Abstract

Background

Increasing number of scientific reports have highlighted the role of histone acetylation/deacetylation in neurodegenerative conditions, including chemotherapy-induced cognitive dysfunction (also known as chemobrain). Multiple sources state that increased activity of histone deacetylases (HDACs) play a detrimental role in chemobrain. In the present study, sodium valproate, a well-known HDAC inhibitor, was explored for its neuroprotective potential against chemobrain development.

Methods

Doxorubicin (DOX), a chemotherapeutic agent, was used to induce chemobrain in experimental animals while treating with sodium valproate simultaneously. The animals were subjected to novel object recognition test (NORT) in order to assess their cognitive status and further, brain antioxidant levels were estimated. The animal body weights and survival were noted throughout the period of the study. Blood parameters such as red blood cell count, white blood cell count and haemoglobin levels were also measured.

Results

Our findings are in contradiction to the known neuroprotective properties of valproic acid. We observed that sodium valproate failed to prevent chemobrain development in DOX treated animals. In fact, treatment with sodium valproate dose dependently worsened cognitive status in DOX treated animals including their brain antioxidant status, possibly leading to neuronal damage through free radical induced toxicity.

Conclusion

The present study highlights the caution that needs to be exercised in projecting HDAC inhibitors as in vivo neuroprotective agents, due to the complexity of existing neurological pathways and the diverse roles of histone deacetylases.

Introduction

Chemotherapy-induced cognitive impairment, termed as chemo-fog or chemobrain, is a recognized clinical syndrome today affecting about 33% of cancer patients treated with chemotherapy [1], [2]. Wagner et al. stated that in cancer patients cognitive deficits due to chemotherapeutic treatment can range from problems with concentration and attention (63%), with memory (50%) and with abstract reasoning (38%) [3]. The condition tends to have a toll on the patients' quality of life as they are left unable to tend to basic activities. To unravel the vague but consistent neurological deficits seen in cancer patients undergoing chemotherapy, ten longitudinal studies have investigated cancer and cognitive dysfunction. These report that 12–82% of such patients have serious cognitive deficits. However, most of these studies have focused on breast cancer patients [2]. Other studies have estimated the percentage of affected individuals to be between 18 and 78% in breast cancer patients, soon after initiation of chemotherapy [4], [5], [6]. Although cancer itself can contribute to cognitive dysfunction, patients often tend to complain of such deficits post-initiation of chemotherapy [7], [8] and around 35% of breast cancer survivors report long-term deficits, even after years of remission [5], [6].

Many chemotherapeutic agents such as 5-fluorouracil, methotrexate, doxorubicin, paclitaxel, cisplatin and cyclophosphamide have been implicated to cause adverse effects on cognitive function in clinically relevant doses, particularly affecting the hippocampal and frontal cortex areas [9], [10]. In-spite of having low potential to cross the blood brain barrier, many antineoplastic agents like doxorubicin (DOX) have the ability to induce systemic release of inflammatory mediators, which can leak into the brain and thereby cause neuronal damage [11], [12].

Histone acetylation has been implicated to have a role in long-term memory. Scientists have demonstrated that loss of histone acetylation activity of proteins like cAMP response element binding protein (CREB) binding protein (CBP) impairs long-term memory in transgenic mice [13]. Additionally, in many neuropsychiatric disorders which have cognitive deficits as a common disability in affected patients, it has been noticed that histone acetylation is reduced. Although there may be various reasons behind the decreased acetylation of histones, one of the contributing factors can be over-activity of histone deacetylases (HDACs). This concept has led to the identification and evaluation of many HDAC inhibitors and their potential as therapeutic agents in neuropsychiatric conditions [14]. Among the known anti-epileptic drugs, valproic acid is known to have HDAC inhibition potential, specifically for class I and class IIa enzymes [15]. Additionally, it is known to exert neuroprotective effects through a variety of mechanisms. For example, valproic acid promotes the expression of brain derived neurotropic factor (BDNF), which facilitates long-term potentiation [16]. It also shows protective effect against glutamate induced- NMDA mediated excitotoxicity. It is known to inhibit glycogen synthase kinase-3 (GSK-3), thereby decreasing amyloid beta protein production, leading to decreased memory impairment [17]. Additionally, valproic acid increases NF-κB signalling, leading to decrease in cell death and increase in proliferation of neural progenitor cells which may lead to increase in neuronal density [18].

In the present study, we have made an attempt to evaluate the therapeutic potential of sodium valproate in prevention of chemobrain development in vivo. Our hypothesis for the study was that sodium valproate can deter the development of chemobrain in DOX treated animals.

Section snippets

Materials

All the chemicals used in this study were of analytical grade. Sodium valproate, DOX, 2-thiobarbituric acid, L-glutathione (reduced), 5,5-dithio-bis (2-nitrobenzoic acid) and adrenaline bitartarate were purchased from Sigma-Aldrich Co. LLC (St. Louis, MO, USA). Carboxymethyl cellulose, sodium dihydrogen phosphate anhydrous, disodium hydrogen phosphate anhydrous, sodium bicarbonate and trichloroacetic acid were purchased from Merck Millipore Corporation (Merck KGaA, Darmstadt, Germany).

Animal experiments

Male

Novel object recognition test (NORT)

NORT was performed in order to assess episodic memory in normal and treated animals [19]. The test results were defined as recognition index (RI) and discriminative index (DI). Animals challenged with DOX only showed significant (p < 0.001) reduction in both recognition index (0.336 ± 0.037 vs. 0.662 ± 0.035 for normal control) and discriminative index (-3.157 ± 1.682 vs. 13.92 ± 1.335 for normal control). Sodium valproate treatment failed to normalize recognition indices at all the doses tested (0.397 ± 

Discussion

Epigenetic alterations have been implicated in the pathogenesis of various conditions, particularly in cancer. Histone acetylation/deacetylation and methylation/demethylation are of particular importance for their alteration in different pathological states. HDAC inhibitors have been mainly developed as anticancer agents. In a recent review on chemobrain, the authors have hypothesized that it is possibly the epigenetic modifications resulting from the change in cytokine levels due to the

Conclusion

Several histone deacetylases have been implicated to have a role in the pathology of neurodegenerative diseases including chemobrain. Since the condition is commonly observed in patients undergoing chemotherapy, the need for a therapy for such a debilitating condition led us to investigate the role of sodium valproate as a histone deacetylase inhibitor, in exerting a protective role to the development of chemobrain in DOX-treated experimental animals. Our study demonstrates the deleterious

6 Acknowledgement

The authors would like to acknowledge the Department of Pharmacology, Manipal College of Pharmaceutical Sciences and Manipal University for providing the infrastructure and financial support required to carry out this research work.

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