eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
Current issue Archive Manuscripts accepted About the journal Editorial board Journal's reviewers Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures
SCImago Journal & Country Rank
vol. 59
Original paper

Memantine improves memory and hippocampal proliferation in adult male rats

Maha Elbeltagy
1, 2
Duha A. Atieh
Basil H. Abdin
Kenan A. S-Yasin
Ahmad M. Abdulraheem
Doaa Qattan
Ahmed S.Salman
1, 2

Department of Anatomy and Histology, Faculty of Medicine, University of Jordan, Amman, Jordan
Department of Anatomy, Faculty of Medicine, Menoufia University, Egypt
Faculty of Medicine, University of Jordan, Amman, Jordan
Folia Neuropathol 2021; 59 (2): 143-151
Online publish date: 2021/06/30
Article file
- Memantine.pdf  [0.35 MB]
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero


According to the World Health Organization (WHO), cancer is the second leading cause of death worldwide after cardiovascular diseases, and it is expected to cause 13.1 million deaths in 2030 [51,56]. Doxorubicin (DOX) is a chemotherapeutic agent that is classified as an anthracycline antitumor antibiotic. It is used in the treatment of many cancers including lung cancer, breast cancer, gastric cancer, paediatric cancer, and multiple myeloma [61]. An estimated 17-75% of cancer patients receiving chemotherapy experience cognitive impairment stemming from agents including DOX [29]. Some patients have shown improved cognition over time after the completion of chemotherapy treatment; however, more than 50% continue to experience impairment [53]. In addition, some animal studies using the novel location recognition (NLR) task have found that chronic exposure to DOX impairs memory function consistently with disrupting hippocampal neurogenesis [8].
The hippocampus, a formation of densely packed neurons in the limbic lobe, plays a fundamental role in learning, memory, and spatial navigation [3,46,60]. It facilitates learning via its connections to the neocortex; in particular, it is involved in acquiring new memories and then solidifying them, thus transforming short-term memory into long-term memory. The hippocampus itself is composed of two major grey matter elements: the cornu ammonis and the dentate gyrus [22]. Each component consists of distinct types of cells that, together with the entorhinal cortex, interact with each other through circuits and contribute to the learning and memory process [2,19,30,49,50]. Furthermore, high expression of NMDA receptors on pyramidal cells is observed in the hippocampus, which are required for spatial memory [44,45].
It is universally accepted that in all adult mammalian brains, there are two sites of high-density cell division: the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation [18]. Hippocampal neurogenesis in adults is of particular interest in our research since it has been shown to significantly influence cognition and the formation of new memories, thereby considerably affecting learning. Several papers have shown that adult hippocampal neurogenesis improves memory and cognition [15,20,33]. Adult hippocampal neurogenesis has also been associated with improved pattern separation, which is increasingly recognized as the underlying mechanism of memory and learning [9,12,58]. Furthermore, brains experiencing a reduction in neurogenesis have shown decreased memory performance, whereas those with increased rates of neurogenesis have displayed increases in cognitive function [13,65].
Memantine (MEM) acts as an NMDA receptor antagonist. Previous studies have shown that NMDA receptor antagonists enhance neurogenesis in the brains of adult rats. Accordingly, MEM is being prescribed by clinicians for the treatment of Alzheimer’s disease (AD). The excitotoxic process that results from overactive NMDA receptors, which is mediated by the excessive influx of calcium during a sustained release of glutamate, has been associated with strokes, trauma, and chronic degenerative diseases such as AD [11]. Memantine has shown a functional role in the improvement of memory and learning processes after neuronal damage, and it prevents the damage from progressing [5,11].
Memantine acts as a neuroprotective agent rather than a disease-reversing agent [64]. In addition, since it has low affinity to the receptor-associated ion channel, it detaches from its binding site relatively quickly. This results in the alleviation of undesired adverse effects as it is not active for prolonged time periods [35]. Hence, we can deduce that MEM does not alter normal brain signalling and can be predicted to be well tolerated in clinical trials [36]. Due to these properties and its unique mechanism of action, clinical trials have been initiated to study the effects of MEM on other forms of dementia, depression, glaucoma, and severe neuropathic pain [36]. Furthermore, MEM’s effect on malignant diseases, like breast and prostate cancer, is being investigated [1,59]. Memantine offers hope for improved quality of life for patients by preventing or at least minimizing the toxic effects of DOX on neural cells and memory. The current study examined the effects of MEM on both memory and hippocampal proliferation in DOX-treated adult male rats.

Material and methods

Ethics statement

All experiments and animal care were performed in accordance with the University of Jordan’s guidelines and with the approval of the local ethics committee. Animals and drug preparations Forty male Sprague-Dawley rats (190-225 g) were bought from the University of Jordan’s animal office and randomly allocated to four groups: control (n = 10), MEM (n = 10), DOX (n = 10), and DOX with MEM (n = 10). The animals were allowed to habituate for two weeks prior to drug administration. Rats in the MEM group were administered 7 i.p. 2.5 mg/kg doses of memantine (Lundbeck, Denmark) every other day. This dose was modified from a study conducted by Cole et al. [10]. Rats in the control group were given an identical volume of 0.9% sterile saline (i.p.). Rats in both the DOX and DOX with MEM groups were administered 7 i.p. 2 mg/kg doses of doxorubicin (EBEWE Pharma, Egypt) every other day. The rats were provided with a 12-hour light/dark cycle (7.00/19.00 h) and free access to food and water.

Behavioural testing

Novel location recognition

In order to test spatial memory, the rats were subjected to the NLR task 30 minutes after the last injection [37]. The NLR task was a spatial variant of a two-trial object recognition task adapted from Dix and Aggleton [14] (see Fig. 1). The apparatus consisted of an arena (a semi-transparent perspex box 49 cm wide × 66 cm long × 40 cm high) and objects (pink, weighted water bottles 15 cm high and 7 cm in diameter). The boxes and the water bottles were cleaned with 20% ethanol prior to each experiment and between trials to remove olfactory cues. A square black card was displayed on the wall of the room during the trials to provide prominent cues for spatial orientation. This apparatus was modified from a previous protocol [14] and was recorded by video camcorder as in our previous study [48]. The procedure consisted of habituating the animals for one hour in the box on the day prior to testing. The following day, as a familiarization trial, two identical objects (water bottles) were placed in separate locations in the box, and the animals were allowed three minutes to explore. The animals were returned to their home cage for a five-minute inter-trial interval, during which the box was cleaned with 20% ethanol. In the choice trial, the animals were returned to the box for three minutes. One object remained in its original position (the familiar location), while the other object was moved to a new position (the novel location) (see Fig. 1). The rat was considered to be exploring the object when it sniffed, licked, or chewed the object or directed its nose at a distance ≤ 1 cm from the object [48]. Exploration was scored based on the total time spent on each object (familiar and novel locations). Data were converted to discrimination indices (DI) which means the time spent exploring the novel object minus the time spent exploring the familiar object divided by total exploration time [6,14,16].

Histology and immunohistochemistry

The day after behavioural testing was completed, the rats were put down by rapid stunning and cervical dislocation. Their brains were extracted, trimmed, and fixed in 3% glutaraldehyde overnight. The next day the brains were sectioned using a Leica vibrating microtome. The 4 um sections were placed onto positively charged slides for routine staining with haematoxylin and eosin and for Ki67 immunohistochemical analysis. The tissues were dewaxed with xylene and rehydrated through a series of graded ethanols. To retrieve the antigens, the samples were autoclaved in 0.01 M sodium citrate, pH 6.0, at 100°C for 20 minutes and then were heated in a microwave oven (800 W) for 5 minutes [55]. Endogenous peroxidase activity was quenched by incubating the slides in H2O2 (3% in methanol) at room temperature for 20 minutes. Non-specific immunoglobulin binding was blocked with 3% bovine serum albumin (manufactured by Merck) in phosphate buffer solution (PBS) at 37°C for 20 minutes.
The polyclonal antibody against Ki67 was bought from Thermofisher, Cat. RB-9043. The primary antibody was diluted in phosphate-buffered saline at a dilution rate of 1 to 50 and incubated at 4°C for 1 h followed by 10 minutes incubation with Goat anti-Rabbit secondary antibody, Thermofisher Cat. A32732 (1 : 250) in PBS for 10 minutes. The slides were counterstained with Mayer’s haematoxylin [55]. A systemic random sampling technique [41] was used to choose every twentieth section throughout the length of the dentate gyrus, selecting 10 sections in total. A Zeiss Primo Star microscope (Oberkochen, Germany) equipped with a Canon EOS 550D camera (Tokyo, Japan) was used to confirm the integrity of the selected sections and for counting the proliferating cells. Counting was done by two independent observers using a double-blind method. Count of Ki67-positive cells was carried out within the SGZ, defined as the zone within three cell diameters of the inner edge of the dentate gyrus (see Fig. 2). Counts from all sections of one dentate gyrus were averaged and multiplied by twenty to provide an estimate of the total number of positive cells in the dentate gyrus [16].

Statistical analysis

Statistical analysis was undertaken and graphs were created using GraphPad Prism 4.0. P < 0.05 was regarded as significant. Student’s paired t-tests were used to compare the exploration times for rats in each group in the NLR task choice trials. A one-way ANOVA with Bonferroni’s post-test was used to compare the number of Ki67-positive proliferating cells and discrimination indices between groups, and a two-way ANOVA with Bonferroni’s post-test was used to compare the replicate means of the rat’s weights over the injection period between all groups.


The effect of treatment on the novel location recognition task

The NLR task shows interactions with objects either in familiar or novel locations within a test arena. During the familiarization trial, in which the rats explored two identical objects, both the control and the treatment groups showed no preference for either object in terms of the total exploration time (data not shown). During the choice trial, in which one object had been moved to a new location, saline, MEM and MEM with DOX injected groups all explored the novel object significantly more than the old location while rats in the DOX group failed to differentiate between the two locations (data not shown). The discrimination index was calculated as the time spent exploring the novel object minus the time spent exploring the familiar object divided by total exploration time and compared between groups (Fig. 3). There was a significant reduction in discrimination index (DI) in the DOX-treated group compared to MEM- (p < 0.001) and MEM with DOX-treated groups (p < 0.001). These findings indicate that the rats treated with MEM along with DOX had protected memory compared to those treated with DOX only and that, compared to MEM treatment, treatment with DOX impaired hippocampal recent memory.

The effect of treatments on proliferating cell counts

There was a significant increase in the total number of Ki67-positive cells in the MEM group compared to the control group (p < 0.05). DOX treatment impaired hippocampal proliferation compared to both saline and MEM treatment (p < 0.001) for both. The DOX with MEM group showed increased hippocampal proliferation compared to the DOX group (p < 0.01). Figure 4 shows these findings correlated with the results obtained from the NLR task.

The effect of different treatments on the rats’ weight

As shown in Figure 5, there was significant difference between groups due to both treatment (p < 0.0001) and injection periods, which are indicated by arrows (p < 0.0001). DOX reduced the weights of the rats after each injection. Overall, there was a significant reduction in weight for rats treated with DOX compared to rats treated with saline throughout the injection period (p < 0.0001). Memantine attenuated this weight loss (p < 0.0001).


This study aimed to assess the effect of MEM on spatial memory and neural proliferation in hippocampus in adult male rats treated with DOX. Previous animal studies have shown that chronic administration of MEM improved spatial cognitive function as evidenced by decreased errors in a Morris water maze [4,42]. This was also suggested to be true in a transgenic mouse model of AD [43]. Pietá Dias et al. demonstrated that chronic MEM administration (20 mg/kg i.p.) over three weeks decreased age-induced spatial memory deficits as investigated through the NLR task. Different test regimens and doses may elucidate this controversy [54]. Enhanced hippocampal proliferation with MEM use was evident in the literature. A study has shown that a single intraperitoneal dose of 50 mg/kg stimulated hippocampal dentate gyrus proliferation in both young and elderly rats [38]. A similar effect was found by Jin et al. [28].
Notably, in our study, the group of rats given seven i.p. injections of DOX failed to recognize the novel location. This finding agrees with previous research showing that DOX disrupted many hippocampal-based memory functions including spatial memory and contextual conditioned fear memory [8,31,63]. In contrast, Fremouw et al. found that DOX-treated mice showed normal contextual fear memory and normal performance in the NLR task when compared to the control group [17]. This may be due to the different dosing regimens and differences in neuronal processes and biological factors between rats and mice. In concordance with our study, DOX-induced cognitive decline may be attributed to decreased hippocampal neurogenesis [8], although one study showed that DOX administration alone did not significantly alter hippocampal neurogenesis unless co-administered with cyclophosphamide [31]. Although the co-administration of MEM with DOX ameliorated DOX-induced cognitive decline and inhibition of hippocampal proliferation, no causal relationship can be deduced based on this observation. Memantine was shown to have other neuroprotective effects like enhancement of synaptic plasticity [67] and inhibition of apoptosis [27]. In addition, recent in vitro studies have demonstrated that MEM ameliorated DOX-induced apoptosis in different types of neuronal cell cultures [25,26]. So further research is encouraged to investigate a causal relationship.
The molecular basis of MEM-induced hippocampal proliferation has not been made clear, although one plausible mechanism is through enhanced BDNF local expression and signalling. This hypothesis is based on a previous finding that MEM caused a dose-related increase in the expression of the BDNF gene, a member of the neurotrophin family, and its receptor TrkB in many cortical regions including the hippocampus [40]. Increasing evidence suggests that increased BDNF levels promote hippocampal neurogenesis in response to different stimuli [24,39,57]. Recent studies have demonstrated that enhanced expression of BDNF contributed to MEM-related enhancement of synaptic plasticity [67] and to the anti-apoptotic effect of MEM [27], but further research is needed to elaborate the effect of BDNF on MEM-induced hippocampal proliferation. Different NMDA receptor antagonists, including MEM, have shown great promise in reversing chemotherapy-induced cognitive deficits in animal models. A study revealed that methotrexate-induced spatial cognitive impairment, which was attributed in part to increased levels of the excitotoxic glutamate analogue homocysteic acid, was ameliorated by the co-administration of MEM [10]. Another NMDA receptor antagonist, Dextromethorphan, has also been shown to decrease negative cognitive outcomes in methotrexate-treated rats [62]. One study showed that MEM mitigated cisplatin-induced impaired performance of rats in the Morris water maze, and it attenuated the cisplatin-related reduction of the expression of PSD95 and ERK1/2 proteins, which are essential for the formation and maintenance of synaptic plasticity [7]. These preclinical data support the hypothesis that NMDA receptor antagonists like MEM may be used for the treatment of chemotherapy-induced cognitive deficits.
Reduction in body weight is a toxic effect associated with the administration of DOX [21,23,34,66]. We noticed a significant weight reduction in the DOX-injected rats in comparison to the control group during the two-week injection period. How-ever, MEM co-treatment effectively improved DOX-induced weight loss. Accordingly, MEM could bea potential agent for the attenuation and prevention of weight loss induced by DOX in clinical practice. This can be partly supported by a randomized controlled trial done on Alzheimer’s patients showing that MEM was associated with a significant increase in body weight when compared to placebo [52]. In addition, two studies have shown that MEM attenuated weight loss in animal models of Huntington’s disease and ulcerative colitis [32,47].


Rats treated with DOX showed a deterioration in memory and an inhibition of cellular proliferation in the hippocampus, in addition to a noticeable decrease in weight. In contrast, the co-administration of MEM and DOX revealed a significant enhancement of memory, a promotion of hippocampal proliferation, plus a remarkable improvement of DOX-induced weight loss.


This work is funded by the deanship of scientific research at the University of Jordan, Jordan.


The authors report no conflict of interest.


1. Albayrak G, Konac E, Dikmen AU, Bilen CY. Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells. Hum Exp Toxicol 2018; 37: 953-958.
2. Amaral DG, Witter MP. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 1989; 31: 571-591.
3. Anand K, Dhikav V. Hippocampus in health and disease: an overview. Ann Indian Acad Neurol 2012; 15: 239-246.
4. Barnes CA, Danysz W, Parsons CG. Effects of the Uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci 1996; 8: 565-571.
5. Beier MT. Treatment strategies for the behavioral symptoms of Alzheimer’s disease: Focus on early pharmacologic intervention. Pharmacotherapy 2007; 27: 399-411.
6. Bruel-Jungerman E, Laroche S, Rampon C. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 2005; 21: 513-521.
7. Cheng J, Liu X, Cao L, Zhang T, Li H, Lin W. Neo-adjuvant chemotherapy with cisplatin induces low expression of NMDA receptors and postoperative cognitive impairment. Neurosci Lett 2017; 637: 168-174.
8. Christie L-A, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 2012; 18: 1954-1965.
9. Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009; 325: 210-213.
10. Cole PD, Vijayanathan V, Ali NF, Wagshul ME, Tanenbaum EJ, Price J, Dalal V, Gulinello ME. Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits. Clin Cancer Res 2013; 19: 4446-4454.
11. Cosman KM, Boyle LL, Porsteinsson AP. Memantine in the treatment of mild-to-moderate Alzheimer’s disease. Expert Opin Pharmacother 2007; 8: 203-214.
12. Creer DJ, Romberg C, Saksida LM, Van Praag H, Bussey TJ. Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A 2010; 107: 2367-2372.
13. Deng W, Aimone JB, Gage FH. New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 2010; 11: 339-350.
14. Dix SL, Aggleton JP. Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition. Behav Brain Res 1999; 99: 191-200.
15. Dupret D, Revest JM, Koehl M, Ichas F, De Giorgi F, Costet P, Abrous DN, Piazza PV. Spatial relational memory requires hippocampal adult neurogenesis. PLoS One 2008; 3: e1959.
16. ElBeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Gloria Tu CY, Bhalla N, Bennett G, Wigmore PM. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res 2010; 208: 112-117.
17. Fremouw T, Fessler CL, Ferguson RJ, Burguete Y. Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment. Behav Brain Res 2012; 226: 154-162.
18. Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-1438.
19. Gold AE, Kesner RP. The role of the CA3 subregion of the dorsal hippocampus in spatial pattern completion in the rat. Hippocampus 2005; 15: 808-814.
20. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 1999; 2: 260-265.
21. Hao G, Yu Y, Gu B, Xing Y, Xue M. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin. Xenobiotica 2015; 45: 1024-1029.
22. Hayman LA, Fuller GN, Cavazos JE, Pfleger MJ, Meyers CA, Jackson EF. The hippocampus: Normal anatomy and pathology. Am J Roentgenol 1998; 171: 1139–1146.
23. Herman EH, Zhang J, Chadwick DP, Ferrans VJ. Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol 2000; 45: 329-334.
24. Hsiao YH, Hung HC, Chen SH, Gean PW. Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis.
25. J Neurosci 2014; 34: 16207-16219.
26. Jantas D, Lason W. Protective effect of memantine against doxorubicin toxicity in primary neuronal cell cultures: influence a development stage. Neurotox Res 2009; 15: 24-37.
27. Jantas D, Pytel M, Mozrzymas JW, Leskiewicz M, Regulska M, Antkiewicz-Michaluk L, Lason W. The attenuating effect of memantine on staurosporine-, salsolinol- and doxorubicin-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurochem Int 2008; 52: 864-877.
28. Jantas D, Szymanska M, Budziszewska B, Lason W. An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons. Apoptosis 2009; 14: 900-912.
29. Jin K, Xie L, Mao XO, Greenberg DA. Alzheimer’s disease drugs promote neurogenesis. Brain Res 2006; 1085: 183-188.
30. Keeney JTR, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM, Sultana R, Saatman KE, St. Clair DK, Butterfield DA. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: Protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”). Oncotarget 2018; 9: 30324-30339.
31. Kesner RP. Behavioral functions of the CA3 subregion of the hippocampus. Learn Mem 2007; 14: 771-781.
32. Kitamura Y, Hattori S, Yoneda S, Watanabe S, Kanemoto E, Sugimoto M, Kawai T, Machida A, Kanzaki H, Miyazaki I, Asanuma M, Sendo T. Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 2015; 292: 184-193.
33. Lee ST, Chu K, Park JE, Kang L, Ko SY, Jung KH, Kim M. Memantine reduces striatal cell death with decreasing calpain level in 3-nitropropionic model of Huntington’s disease. Brain Res 2006; 1118: 199-207.
34. Leuner B, Gould E, Shors TJ. Is there a link between adult neurogenesis and learning? Hippocampus 2006; 16: 216-224.
35. de Lima Junior EA, Yamashita AS, Pimentel GD, De Sousa LGO, Santos RVT, Gonçalves CL, Streck EL, de Lira FS, Rosa Neto JC. Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. J Cachexia Sarcopenia Muscle 2016; 7: 615-625.
36. Lipton S. Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation. Curr Drug Targets 2007; 8: 621-632.
37. Lipton S. The molecular basis of memantine action in Alzheimers disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2005; 2: 155-165.
38. Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 2017; 2017: 1-9.
39. Maekawa M, Namba T, Suzuki E, Yuasa S, Kohsaka S, Uchino S. NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus. Neurosci Res 2009; 63: 259-266.
40. Marlatt MW, Potter MC, Lucassen PJ, van Praag H. Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol 2012; 72: 943-952.
41. Marvanová M, Lakso M, Pirhonen J, Nawa H, Wong G, Castrén E. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci 2001; 18: 247-258.
42. Mayhew TM, Burton GJ. Methodological problems in placental morphometry: apologia for the use of stereology based on sound sampling practice. Placenta 1988; 9: 565-581.
43. Minkeviciene R, Banerjee P, Tanila H. Cognition-enhancing and anxiolytic effects of memantine. Neuropharmacology 2008; 54: 1079-1085.
44. Minkeviciene R, Banerjee P, Tanila H. Memantine improves spatial learning in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 2004; 311: 677-682.
45. Morris RGM, Garrud P, Rawlins JNP, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; 297: 681-683.
46. Morris RGM, Hagan JJ, Rawlins JNP. Allocentric spatial learning by hippocampectomised rats: a further test of the “spatial mapping” and “working memory” theories of hippocampal function. Q J Exp Psychol Sect B 1986; 38: 365-395.
47. Moser EI, Kropff E, Moser MB. Place cells, grid cells, and the brain’s spatial representation system. Annu Rev Neurosci 2008; 31: 69-89.
48. Motaghi E, Hajhashemi V, Mahzouni P, Minaiyan M. The effect of memantine on trinitrobenzene sulfonic acid-induced ulcerative colitis in mice. Eur J Pharmacol 2016; 793: 28-34.
49. Mustafa S, Walker A, Bennett G, Wigmore PM. 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 2008; 28: 323-330.
50. Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci 2004; 5: 361-372.
51. Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A, Carr CA, Johnston D, Wilson MA, Tonegawa S. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 2002; 297: 211-218.
52. Padma VV. An overview of targeted cancer therapy. Biomed 2015; 5: 1-6.
53. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006; 14: 704-715.
54. Philpot RM, Ficken M, Johns BE, Engberg ME, Wecker L. Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors. Cancer Chemother Pharmacol 2019; 84: 579-589.
55. Pietá Dias C, Martins de Lima MN, Presti-Torres J, Dornelles A, Garcia VA, Siciliani Scalco F, Rewsaat Guimarães M, Constantino L, Budni P, Dal-Pizzol F, Schröder N. Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats. Neuroscience 2007; 146: 1719-1725.
56. Pisamai S, Rungsipipat A, Kunnasut N, Suriyaphol G. Immunohistochemical expression profiles of cell adhesion molecules, matrix metalloproteinases and their tissue inhibitors in central and peripheral neoplastic foci of feline mammary carcinoma. J Comp Pathol 2017; 157: 150-162.
57. Rivankar S. An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther 2014; 10: 853-858.
58. Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, Fabbri ME, Tessarollo L, Maffei L, Berardi N, Caleo M. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci 2006; 24: 1850-1856.
59. Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011; 472: 466-470.
60. Seifabadi S, Vaseghi G, Javanmard SH, Omidi E, Tajadini M, Zarrin B. The cytotoxic effect of memantine and its effect on cytoskeletal proteins expression in metastatic breast cancer cell line. Iran J Basic Med Sci 2017; 20: 41-45.
61. Squire LR. Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 2004; 82: 171-177.
62. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011; 21: 440-446.
63. Vijayanathan V, Gulinello M, Ali N, Cole PD. Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res 2011; 225: 491-497.
64. Wagawade JD, Roy S, Hullatti K, Khode NR, Pednekar H, Hegde H V., Kholkute SD. Doxorubicin induced cognition impairment in rat model. Asian J Pharm Clin Res 2015; 8: 301-304.
65. Williams BS, Buvanendran A. Memantine. In: Sinatra RS, Jahr JS, Watkins-Pitchford JM, (Eds.). The Essence of Analgesia and Analgesics. Cambridge University Press, Cambridge 2010; pp. 319-320.
66. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132: 645-660.
67. Zhao X, Zhang J, Tong N, Liao X, Wang E, Li Z, Luo Y, Zuo H. Berberine attenuates doxorubicininduced cardiotoxicity in mice. J Int Med Res 2011; 39: 1720-1727.
68. Zhu G, Li J, He L, Wang X, Hong X. MPTP-induced changes in hippocampal synaptic plasticity and memory are prevented by memantine through the BDNF-TrkB pathway. Br J Pharmacol 2015; 172: 2354-2368.
Copyright: © 2021 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2021 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.