Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy

Abstract

The chemotherapy drug, 5-fluorouracil (5-FU), has been reported to cause cognitive impairments in cancer patients. The drug also reduces cell proliferation and survival in the brain. Asiatic acid (AA) is a triterpene compound found in Centella asiatica that can protect against reduction of neurogenesis in the hippocampus and memory deficits induced by valproic acid (VPA). In the present study, we investigated the preventive effects of AA on the deficits in spatial working memory and cell proliferation and survival caused by 5-FU chemotherapy in a rat model. Male Sprague Dawley rats received 5-FU (5 i.v. injections, 25 mg/kg) on day 8, 11, 14, 17 and 20 of the study. This was co-administered with AA (30 mg/kg, oral gavage tube) either 20 days before receiving 5-FU (preventive), after receiving 5-FU (recovery), or for the entire period of the experiment (throughout). Spatial working memory was determined using the novel object location (NOL) test and hippocampal cell proliferation and survival of dividing cells were quantified using immunohistochemistry. Rats in the 5-FU alone and recovery groups showed memory deficits in the NOL test and reductions in cell proliferation and cell survival in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Rats in the control, AA alone, and both preventive and throughout co-administration groups, however, did not exhibit these characteristics. The results showed that 5-FU chemotherapy impaired memory and reduced cell proliferation and cell survival in the SGZ of the hippocampal dentate gyrus. However, these impairments in the animals receiving 5-FU chemotherapy were restored to control levels when AA was co-administered before and during 5-FU treatment. These data demonstrate that AA can prevent the spatial working memory and hippocampal neurogenesis impairments caused by 5-FU chemotherapy.

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice

“…The OLM is a hippocampal‐dependent test of location memory (Assini, Duzzioni, & Takahashi, ; Cipolotti, ) which is known to be impaired with aging in both humans and rodents (Arias‐Cavieres, Adasme, Sánchez, Muñoz, & Hidalgo, ; Sapkota, van der Linde, Lamichhane, Upadhyaya, & Pardhan, ; Wimmer, Hernandez, Blackwell, & Abel, ). The improvement in the OLM seen in this study is consistent with previous studies showing that asiatic acid, a major triterpene component of Centella asiatica (Siddiqui, Aslam, Ali, Khan, & Begum, ), improves performance in the same task in healthy as well as cognitively impaired rodents (Chaisawang et al., ; Sirichoat et al., ; Umka Welbat et al., ). It is also in line with reports that OLM performance by aged mice is improved by treatment with polyphenols (Carey, Gomes, & Shukitt‐Hale, ; Matsui et al., ), a class of compounds which both Centella asiatica in general (Siddiqui et al., ; Subban, Veerakumar, Manimaran, Hashim, & Balachandran, ) and CAW specifically are rich in (Gray, Zweig, Matthews, et al., ; Gray, Zweig, Murchison, et al., ; Soumyanath et al., ).…”

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

“…The clinical use of a chemotherapeutic drug, 5-fluorouracil is often compromised due to potential cognitive impairments in patients. AA corrected impairment in spatial working memory and neurogenesis in rats receiving 5-FU (Chaisawang et al, 2017 ). AA improved spatial memory in novel object location test subsequent to a reduction in proliferation and survival of cells in the subgranular zone of the hippocampal dentate gyrus (Chaisawang et al, 2017 ).…”

“…AA corrected impairment in spatial working memory and neurogenesis in rats receiving 5-FU (Chaisawang et al, 2017 ). AA improved spatial memory in novel object location test subsequent to a reduction in proliferation and survival of cells in the subgranular zone of the hippocampal dentate gyrus (Chaisawang et al, 2017 ). The studies are suggestive of the protective effects of AA on chemotherapy-associated adverse effects.…”

A Review on Medicinal Properties of Centella Asiatica

“…Asiatic acid was found to prevent spatial working memory and reduction of neurogenesis defects in the hippocampal region caused by 5-FU chemotherapy [72]. Water extract of C. asiatica was observed to enhance synaptic differentiation and dendritic arborization with reference to Aβ which causes cognitive improvement [73].…”