Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions.

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.

[Non-specific symptoms of inflammation in its experimental models: influence of interleukin-1]. / Nespecifické projevy zánetu v jeho experimentálnich modelech: vliv interleukinu 1.

The local signs of inflammation are redness, oedema, increased temperature and pain. Local inflammatory changes are often followed by systemic non- specific alterations. Fever, which is usually the first sign of systemic inflammation, is accompanied by other systemic inflammatory changes like pain and anorexia. The systemic non-specific inflammatory symptoms also include changes in general activity, cognition, and affection. Sickness behaviour syndrome increases survival of the organism affected by inflammation. Many of sickness symptoms are regulated centrally by the brain. IL-1beta holds a privilege in regulation of sickness symptoms.

Transient anorexia, hyper-nociception and cognitive impairment in early adjuvant arthritis in rats.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with enhanced pro-inflammatory cytokine levels, pain, anorexia, and cognitive changes. The enhanced production of cytokines appears before the full manifestation of the disease. So far, any experimental data on behavioral effects of early arthritis are lacking. In the present series we describe anorexia early changes in, pain hyper-sensitivity and altered cognitive behavior during the first four days of adjuvant arthritis in rats (AA), when no clinical signs are yet apparent. METHODS: AA was induced to male Lewis rats by a single injection of complete Freund's adjuvant (cFA) at the base of the tail. Plasma leptin and ghrelin were measured using specific RIA methods. Gene expressions for food-regulatory peptides, neuropeptide-Y (NPY) and interleukin-1ß (IL-1ß) in the hypothalamic arcuate nuclei (nARC), were quantitated by TaqMan real-time PCR. Pain sensation was measured on all four limbs and tail by the plantar test. Cognitive functions were tested in the Morris water maze (MWM). RESULTS: Levels of orexigenic ghrelin as well as mRNA expression of orexigenic NPY in nucleus arcuatus (nRC)re significantly enhanced on day 2 of AA only. Reduced body weight and food intake persisted by day 4 with the most profound reduction on day 2. The mRNA for anorexigenic IL-1ß in the nARC was significantly enhanced on days 2 and 4. Enhanced pain sensitivity was observed on day 2, as was the cognitive impairment given by longer time to find the hidden platform, longer time spent in thigmotaxis zone, and longer trajectory. The less effective strategy used to find the hidden platform was observed up to the day 4 of AA. CONCLUSIONS: Early stage of AA brings about reduced body weight, food intake, and activation of central orexigenic pathways. The observed anorexia could be ascribed to the over-expression of anorexigenic IL-1ß which dominates over the NPY orexigenic effects. On day 2 of AA higher pain sensitivity and cognitive impairment appear. All the observed change tend to recover by day 4 of the disease.

Activation of hypothalamic NPY, AgRP, MC4R, AND IL-6 mRNA levels in young Lewis rats with early-life diet-induced obesity.

OBJECTIVE: Obesity represents a low-grade inflammatory disease and appears a risk factor for insulin resistance, but little is known on whether this may contribute to the development of autoimmune inflammatory diseases. The aim of this work was to study the early-life diet-induced obesity in Lewis rats which are known to be highly susceptible to autoimmunity. METHODS: Obesity was induced by reduced litter size (4 pups per litter) followed by high-fat diet (SHF rats). Control rats (8 pups per litter) were fed with standard diet (CN rats). Oral glucose tolerance test (3 g glucose per kg b.w.) was performed by intra-gastric tube in conscious rats after 12 h fast. Adipocyte size was assessed by light microscope after collagenase digestion. Hypothalamic arcuate (ARC) and paraventricular nuclei (PVN) were isolated by the punching technique. Target mRNAs were quantified by real-time PCR with the use of TaqMan probes and primers. Serum hormones (leptin, ghrelin, adiponectin, visfatin and insulin) were assayed by specific RIAs . RESULTS: During the experimental period SHF rats had the same body weight gain and caloric intake as CN rats. At the age of 8 weeks SHF rats showed increased epididymal fat mass and adipocyte volume, impaired glucose tolerance, normal basal fasting insulin, visfatin, and ghrelin level, but decreased adiponectin and high leptin level. In the ARC, the SHF rats showed increased expression of mRNA for orexigenic neuropeptide Y (NPY), agouti-related protein (AgRP) and anorexigenic pro-inflammatory cytokine IL-6. In the PVN, the SHF rats showed increased expression of mRNA for anorexigenic melanocortin 4 receptor (MC4R) and IL-6. CONCLUSION: Overexpression of orexigenic NPY and AgRP in the ARC indicates leptin resistance in SHF rats. The increased expression of MC4R in PVN points to the activation of melanocortin anorexigenic system which, along with increased hypothalamic IL-6, might prevent the animals from overfeeding. Higher adiposity in these rats results from the high fat-diet composition and not from increased caloric intake. Furthermore, enhanced leptin production appears the main factor indicating the predisposition to autoimmunity in these overfed rats.