Galantamine mitigates neurotoxicity caused by doxorubicin via reduced neuroinflammation, oxidative stress, and apoptosis in rat model.

OBJECTIVE: Doxorubicin (DXR) is commonly used as a drug for cancer treatment. However, there have been reports of neurotoxicity associated with chemotherapy. Galantamine (GLN) is a medication that inhibits cholinesterase activity, providing relief from the neurotoxic effects commonly seen in individuals with Alzheimer's disease. This study explored the potential ameliorative effect of GLN on brain neurotoxicity induced by DXR. MATERIALS AND METHODS: Forty rats were allocated into four separate groups for a study that lasted for a period of fourteen days. The control group was given normal saline, DXR group was given 5 mg/kg DXR every three days (cumulative dose of 20 mg/kg) through intraperitoneal injection. The GLN group was given 5 mg/kg GLN through oral gavage daily, while the DXR+GLN group was given DXR+GLN simultaneously. An analysis of brain proteins using ELISA to assess apoptosis through the concentration of inflammation and oxidative injury markers. RESULTS: The DXR treatment led to increased neuroinflammation by elevation of nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2), oxidative stress by rise of malondialdehyde (MDA), and decline of superoxide dismutase (SOD), and no changes in catalase and glutathione (GSH), cell death by elevation of Bax and caspase-3 and reduced Bcl-2, and increase lipid peroxidation, impaired mitochondrial function. When GLN is administered alongside DXR, it has been observed to positively impact various biological markers, including COX-2, NF-κB, MDA, SOD, Bax, Bcl-2, and caspase-3 levels. Additionally, GLN improves lipid peroxidation and mitochondrial activity. CONCLUSIONS: DXR therapy in rats results in the development of neurotoxicity, and a combination of GLN can recover these toxicities, suggesting GLN promising evidence for mitigating the neurotoxic effects induced by DXR.

Metformin's effect on male rats experiencing CMF-induced neurotoxicity.

OBJECTIVE: Numerous cancers are treated with the chemotherapy drugs cyclophosphamide (CP), methotrexate (MT), and fluorouracil (FU). However, it should be noted that neurotoxicity is a possible side effect of chemotherapy. The pharmaceutical agent metformin (MTF) is used to control type 2 diabetes. The administration of MTF has been documented to exhibit a reduction in specific toxic effects associated with chemotherapy. The primary purpose of this research was to examine whether MTF could mitigate the neurotoxicity brought on by cranial magnetic field (CMF). MATERIALS AND METHODS: A cohort of forty male rats was divided into four distinct groups, with ten animals in each. We classified them as either saline, MTF, CMF, or CMF+MTF. The rats in the experiment group received two doses of CMF via intraperitoneal injection and were also given MTF in their drinking water at a concentration of 2.5 mg/mL on a daily basis. Brain tissue was obtained for ELISA of Bax, Bcl-2, and caspase-3 expression, as well as to determine NMDA and AMPA receptor mRNA expression by real-time polymerase chain reaction (RT-PCR) analysis. RESULTS: Expression of AMPAR, NMDAR, Bax, Bcl-2, and caspase-3 was not notably different between the saline and MTF groups. In contrast, mRNA expression for AMPAR, NMDAR, Bax, and caspase-3 was notably upregulated in the CMF group, while Bcl-2 was downregulated. The co-administration of MTF and CMF did not mitigate these side effects. CONCLUSIONS: neurotoxicity was induced in rats by CMF treatment, but the elevation of the glutamatergic system and the elevation of apoptotic proteins were not prevented by the MTF co-treatment.

Nilotinib treatment induces cognitive impairment by elevating hippocampal oxidative stress in rats.

OBJECTIVE: Protein tyrosine kinases (TKs) play a critical role in the regulation of various functions of a cell, including cellular proliferation, differentiation, and growth, and inhibitors of TKs have emerged as next-generation therapeutic agents in various types of cancer. Nilotinib, one of the TK inhibitors used to treat chronic myeloid leukemia, has been poorly investigated for its potential impact on memory function despite its ability to cross the blood-brain barrier (BBB). Thus, in this study, we investigated the effect of nilotinib on hippocampal-dependent cognitive functions and its potential mechanisms. MATERIALS AND METHODS: Wistar albino male rats were divided into three groups of 10 each. The animals of group I (normal control) received drinking water only, while groups II and III were treated with nilotinib at doses of 15 mg/kg and 30 mg/kg, p.o. respectively, once daily for two weeks. The animals were subjected to behavioral tests after completion of drug treatment for the assessment of cognitive function using the Y-maze, novel object recognition (NOR) test, and elevated plus maze (EPM). The animals were euthanized after the estimation of blood glucose, and hippocampal tissues were dissected for the estimation of markers of oxidative stress. RESULTS: Nilotinib produced impairment of memory function on the Y-maze, NOR test, and EPM. These results were also supported by a significant increase in glutathione (GSH), malondialdehyde (MDA), Akt, glycogen synthase kinase-3 beta (GSK3ß), and total antioxidant capacity (TAC) in hippocampal tissue without altering the blood glucose level. CONCLUSIONS: Nilotinib treatment produced significant impairment of cognitive function by inducing oxidative stress in the hippocampal tissue of rats.

Mechanisms underlying cognitive impairment induced by prenatal cannabinoid exposure: a literature review.

Human and animal studies have revealed that prenatal cannabinoid exposure alters fetal brain development and leads to persistent impairment in the cognitive function of offspring. However, the mechanism underlying the effect of prenatal cannabinoid exposure on cognitive function in offspring is still not fully understood. Therefore, the goal of this literature review is to discuss the published studies on the mechanisms underlying the effects of prenatal cannabinoid exposure on cognitive impairment. The articles used in this prenatal cannabinoid exposure review were retrieved by electronic search of the Medline database for literature describing human and animal models of prenatal cannabinoid exposure from 2006 to 2022. The findings from the studies reviewed revealed that the cognitive impairment associated with prenatal cannabinoid exposure is caused by alterations in the expression and function of endocannabinoid receptor 1 (CB1R), decreased glutamate transmission, reduced neurogenesis, alterations in protein kinase B (PKB/Akt) and extracellular signal­regulated kinase 1 and 2 (ERK1/2) activity, and increased mitochondrial function in the hippocampus, cortex, and cerebellum. This review briefly touches upon the currently available measurement and prevention methods and their limitations.

Effects of CMF and MET on glutamate and dopamine levels in the brain, and their impact on cognitive function.

OBJECTIVE: Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity. MATERIALS AND METHODS: Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC). RESULTS: Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group. CONCLUSIONS: Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.

Ciproxifan attenuates the memory impairment induced by lipopolysaccharide through modulation of cholinergic transmission in the mouse brain.

OBJECTIVE: We investigated the protective effect of ciproxifan on lipopolysaccharide (LPS)-induced memory impairment by altering the cholinergic system in a mouse model. MATERIALS AND METHODS: Groups of mice were given ciproxifan (1 or 3 mg/kg, p.o.) for 30 days. Neurotoxicity was induced with four doses of LPS (250 µg/kg, i.p.) from day-22 to day-25 of drug treatment in three groups. Then, mice were subjected to behavioral assessments using tests [elevated plus maze (EPM), novel object recognition (NOR), and Y-maze]. Also, brain tissues were collected for estimation of cholinergic transmission [acetylcholine (ACh) and acetylcholinesterase (AChE) levels]. RESULTS: Ciproxifan could rescue the memory impairment caused by LPS by shortening the transfer latency in the EPM test, increasing the time spent to explore a novel object and increasing the Discrimination Index in the NOR test and increasing the number of entries to the novel arm and duration of time spent in the novel arm in the Y-maze test. Ciproxifan increased the levels of ACh by decreasing AChE activity in LPS-treated mice. CONCLUSIONS: Ciproxifan treatment can improve memory impairment in mice by increasing ACh levels and decreasing AChE levels.

Elucidating the mechanism underlying cognitive dysfunction by investigating the effects of CMF and MET treatment on hippocampal neurons.

OBJECTIVE: Chemotherapy causes long-term cognitive impairment in cancer survivors. A combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) (i.e., CMF) is widely used for cancer treatment. Metformin (MET), an oral antidiabetic drug, confers protection against the adverse effects of chemotherapeutic agents, such as CYP. To elucidate the potential mechanism underlying cognitive dysfunction, we investigated the impact of CMF and MET treatment on the activities of mitochondrial respiratory chain complexes I and IV, as well as lipid peroxidation, in hippocampal neurons. MATERIALS AND METHODS: Hippocampal neurons (H19-7) cells were treated for 24 h with MET (0.5 mM) alone; CYP (1 µM), MTX (0.5 µM), and 5-FU (1 µM); and MET (0.5 mM) + CYP (1 µM), MTX (0.5 mM), and 5-FU (1 µM). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay was performed to evaluate cell survival. Neurons were collected and homogenized in a neuronal lysis buffer to assess mitochondrial complexes (I and IV) activity and lipid peroxidation. RESULTS: Compared to the control, MET-treated cells showed no significant difference in survival rate; however, CMF- and CMF + MET-treated cells showed a significant reduction in survival rate. In addition, relative to the control, CMF- and CMF + MET-treated cells showed a reduction in mitochondrial complex I activity, whereas no significant changes were observed in mitochondrial complex IV activity. MET-treated cells showed no significant differences in lipid peroxidation, but CMF- and CMF + MET-treated cells showed a slight increase in lipid peroxidation. CONCLUSIONS: The reduction in the activity of mitochondrial complex I and a slight increase in lipid peroxidation levels may explain the cognitive impairment following CMF and MET treatments.

Organophosphates modulate tissue transglutaminase activity in differentiated C6 neural cells.

OBJECTIVE: The organophosphate compounds chlorpyrifos (O, O-diethyl O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate, CPF) and phenyl saligenin phosphate (PSP) have been widely implicated in developmental neurotoxicity and neurodegeneration. However, the underlying mechanism remains unclear. Transglutaminase (TG)2 is a calcium ion (Ca2+)-dependent enzyme with an important role in neuronal cell outgrowth and differentiation and in neurotoxin activity and is modulated by organophosphates. MATERIALS AND METHODS: We studied TG2 activity modulation by CPO and PSP during differentiation in C6 glioma cells. We studied the effects of CPO or PSP treatment with or without the TG2 inhibitor Z-DON and identified potential TG2 protein substrates via mass spectrometry. RESULTS: PSP and CPO did not affect cell viability but affected TG2 activity in differentiating cells. Our results indicate that the organophosphate-induced amine incorporation activity of TG2 may have a direct effect on neuronal outgrowth, differentiation, and cell survival by modifying several essential microtubule proteins, including tubulin. Inhibiting TG2 reduced neurite length but not cell survival. CONCLUSIONS: TG2 inhibitors can protect against organophosphate-induced neuropathy and could be used for developing novel therapeutic strategies for treating brain cancer and neurodegenerative disorders.

Recent progress in the elucidation of the mechanisms of chemotherapy-induced cognitive impairment.

The term "chemobrain" refers to the cognitive dysfunction that occurs after chemotherapy, and it is also known as chemotherapy-induced cognitive impairment or "chemofog". The aim of this review is to bring together the findings of existing literature on the topic and summarize the current knowledge on the potential mechanisms of chemobrain. According to the reviewed studies, the mechanisms by which chemotherapy could cause chemobrain include disruption of hippocampal cell proliferation and neurogenesis, hormonal changes, increased oxidative stress and reactive oxygen species production, chronic increase in inflammation, and alterations in synaptic plasticity and long-term potentiation. While the effects of inflammation and oxidative stress on neurogenesis and their role in chemotherapy-induced cognitive impairment have been widely studied, the chemotherapy-induced cognitive impairment mechanisms that involve mitochondrial dysfunction, estrogen dysregulation, and increased transglutaminase 2 are still unclear. Further studies on these mechanisms are necessary to understand the effects of chemotherapy at the cellular and molecular level and facilitate the development of preventive and therapeutic strategies against chemotherapy-associated cognitive impairment or chemobrain.

CMF and MET treatment induce cognitive impairment through upregulation of IL-1α in rat brain.

OBJECTIVE: Cyclophosphamide (CYP), methotrexate (MTX) and 5-fluorouracil (5-FU) (CMF) are chemotherapeutic agents known to cause acute and long-term cognitive impairment in cancer patients. Cognitive function is regulated mainly by neuronal circuitry in the brain, especially the cortex and hippocampus as well as other components of the limbic area. Neuroinflammation mediated by proinflammatory cytokines is a well-known cause of cognitive impairment. Our previous study showed that metformin induced cognitive impairment and neuroinflammation in CMF-treated rats. Understanding the effects and mechanisms of CMF and MET treatment on chemotherapy-related cognitive impairment and the relationship with neuroinflammation may help prevent some of the adverse effects of this type of chemotherapy in cancer patients. MATERIALS AND METHODS: Rats were divided into four groups: control (normal saline), CMF (50 mg/kg CYP, 2 mg/kg MTX, 50 mg/kg 5-FU; two doses administered by intraperitoneal injection over two weeks), MET (2.5 mg/ml - oral administration daily), and CMF+MET group. IL-1α, IRS-1, Akt-a and TNF-α levels in brain tissues were measured by ELISA and data were analyzed by one-way ANOVA test followed by Tukey's test. RESULTS: Compared with the control group, IL-1α levels were significantly increased in the CMF+MET group, whereas there were no significant differences in the MET and CMF groups. On the other hand, IRS-1, TNF-α and Akt-a expression and mitochondrial complex 1 activity indicated that systemic CMF and MET treatment did not change the expression of these proteins in the brain compared to the control group. CONCLUSIONS: Our results indicate that cognitive function is impaired by the administration of two doses of CMF and MET over a period of two weeks as a result of IL-1α overexpression in the brain.

DOX and MET treatment induces cognitive impairment through downregulation of IL-1-alpha and IRS-1 in the rat brain.

OBJECTIVE: Chemotherapeutic drugs are effective in the treatment of various types of cancers. However, the secondary side effects of chemotherapy, such as cardiotoxicity, hepatotoxicity, and cognitive impairment, limit its clinical effectiveness in cancer treatment. The present study was aimed at investigating the effects of doxorubicin (DOX) on cognitive impairment through its effects on interleukin (IL)-1, insulin receptor substrate 1 (IRS-1), IL-6, Akt, and tumor necrosis factor (TNF)-alpha expression. MATERIALS AND METHODS: Rats were treated with DOX, metformin (MET), and DOX+MET, and IL-1, IRS-1, IL-6, Akt, and TNF-alpha expression levels were assessed using Enzyme-Linked Immunosorbent Assay kits. RESULTS: The DOX-treated rats showed significantly decreased IL-1 and IRS-1 expression in the brain, and the expression of these proteins was rescued on MET administration. On the other hand, IL-6, protein kinase B (PKB/Akt), and TNF-alpha expression was unaltered in the brain of DOX- and MET-treated rats. CONCLUSIONS: Our findings showed that DOX induces cognitive impairment by modulating IL-1-alpha and IRS-1 expression and that MET administration failed to rescue the DOX-mediated memory impairment.

Mechanisms underlying cognitive impairment induced by prenatal caffeine exposure.

OBJECTIVE: Caffeine is one of the most commonly used stimulants among pregnant women. Human and animal studies have shown that prenatal caffeine exposure affects fetal brain development and results in persistent cognitive deficits in offspring. Studies have found that caffeine consumption during pregnancy may alter many activities that are ultimately associated with cognitive dysfunction in offspring. Despite these important findings, there is a fundamental gap in understanding the mechanism underlying cognitive impairment due to prenatal caffeine exposure. Filling this knowledge gap would provide further insights into caffeine-mediated cognitive dysfunction. The objective of this review was to evaluate the findings of studies showing that prenatal caffeine exposure induces cognitive dysfunction and the potential underlying mechanisms.

Co-administration of imipramine and doxorubicin reduces the survival rate and body weight of mice.

OBJECTIVE: Doxorubicin (DOX) is a chemotherapeutic agent widely used to treat cancers, particularly breast cancer. DOX has side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity. Imipramine is an antidepressant that increases the release of neurotransmitters. This study aimed to investigate the effect of co-administration of imipramine and DOX on DOX-induced toxicity. MATERIALS AND METHODS: Forty female mice (10-12-weeks-old, 30-38 g) were divided into four groups (n = 10 per group). The animals in the control group received a single-dose saline injection. The animals in the DOX group received a single dose of DOX (20 mg/kg) by intraperitoneal (i.p.) injection. The animals in the imipramine group received the drug daily in their drinking water (0.13 mg/mL) for 9 days, starting 1 day before the DOX injection received by the DOX group. The animals in the combination group (DOX+imipramine) received a single dose of DOX (20 mg/kg, i.p. injection), and a daily dose of imipramine in their drinking water (0.13 mg/mL) for 9 days starting 1 day before the DOX injection. The animals were observed daily to record mortality, and their body weights were recorded every alternate day. RESULTS: DOX treatment increased the rate of mortality compared with that for control animals. Imipramine co-administration with DOX increased the rate of mortality significantly (p < 0.05) compared with DOX treatment alone. The mortality rate in both the control and imipramine-treatment groups was zero. DOX co-administered with imipramine resulted in significantly reduced body weight compared with control animals. CONCLUSIONS: The combination of DOX and imipramine reduced the survival rate of female mice, suggesting that imipramine increases the toxic effects of DOX.

Effect of inhaled waste anaesthetic gas on blood and liver parameters among hospital staff.

A significant health risk exists within a section of health workers that are exposed to anaesthetic gas and vapours, found in the atmosphere of treatment or operating rooms. These compounds are classified as waste anaesthetic gases (WAG). The present study aimed at identifying alterations in hepatic and haematological parameters occurring as a result of chronic exposure to WAG potentially affecting the health of team members working in hospitals. Therefore, operating room operatives, vulnerable to long-standing WAG exposure, were recruited for this study. Sevoflurane anaesthesia metabolites (inorganic fluoride and hexafluoroisopropanol (HFIP)), haematological indices and liver toxicity markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and osteopontin) were measured. The collected results showed increased plasma inorganic fluoride, HFIP and liver toxicity markers, as well as disturbances in haematological parameters. In conclusion, exposure to halogenated inhalational anaesthetics, in general, and Sevoflurane, in particular, induces alterations in hepatic markers and haematological indices.