Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. While the effect of regular exercise has been studied, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviors in approximately 25% of patients with DMD, possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of Duchenne muscular dystrophy (DMD). Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating KYNA and KYNA:KYN ratio compared with their respective wild-type (WT) controls. Moreover, only D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of their cages during a novel object recognition test when compared with WT. Along with this, we found that muscles from D2 mdx mice had less peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and kynurenine amino transferase-1 enzyme content as well as elevated expression of inflammatory cytokines compared with WT muscles. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.

The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe2+/Fe3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe2+/Fe3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe2+/Fe3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.

Cirsium japonicum var. Maackii Improves Cognitive Impairment under Amyloid Beta25-35-Induced Alzheimer’s Disease Model

Abnormal production and degradation of amyloid beta (Aβ) in the brain lead to oxidative stress and cognitive impairment in Alzheimer’s disease (AD). Cirsium japonicum var. maackii (CJM) is widely used as an herbal medicine and has antibacterial and anti-inflammatory properties. This study focused on the protective effect of the ethyl acetate fraction from CJM (ECJM) on Aβ25-35-induced control mice. In the T-maze and novel object recognition test, ECJM provided higher spatial memory and object recognition compared to Aβ25-35 treatment alone. In the Morris water maze test, ECJM-administered mice showed greater learning and memory abilities than Aβ25-35-induced control mice. Additionally, ECJM-administered mice experienced inhibited lipid peroxidation and nitric oxide production in a dose-dependent manner. The present study indicates that ECJM improves cognitive impairment by inhibiting oxidative stress in Aβ25-35-induced mice. Therefore, CJM may be useful for the treatment of AD and may be a potential material for functional foods.

Selenomethionine Ameliorates Cognitive Impairment, Decreases Hippocampal Oxidative Stress and Attenuates Dysbiosis in D-Galactose-Treated Mice

The prevalence of age-related cognitive impairment is increasing as the proportion of older individuals in the population grows. It is therefore necessary and urgent to find agents to prevent or ameliorate age-related cognitive impairment. Selenomethionine (SeMet) is a natural amino acid occurring in yeast and Brazil nuts. It mitigates cognitive impairment in an Alzheimer’s disease mouse model, however, whether it works on age-related cognitive impairment remains unknown. In this study, SeMet significantly improved the performance of D-galactose-treated mice in the novel object recognition test, passive avoidance task and Morris water maze test. SeMet reversed D-galactose-induced reduction of hippocampal acetylcholine levels, suppression of choline acetyltransferase activity and activation of acetyl cholinesterase. It decreased D-galactose-induced oxidative stress and increased the selenoprotein P levels in the hippocampus. Besides, it attenuated D-galactose-induced dysbiosis by increasing the α-diversity and modulating the taxonomic structure. Correlations between certain taxa and physiological parameters were observed. Our results provide evidence of the effectiveness of SeMet on ameliorating D-galactose-induced cognitive impairment and suggest SeMet has potential to be used in the prevention or adjuvant treatment of age-related cognitive impairment.

Evaluation of Memory Impairment Following Prenatal Exposure to Mosquito Coil Smoke

Background: Developmental Neurotoxicity can lead to the buildup of reactive oxygen species which is an indicator to oxidative stress in the prenatally exposed offspring. Neuronal oxidative stress induces neuroinflammation, precedes tangle formation, and disrupts synaptic plasticity. The result of such changes may be expressed into adulthood as behavioral deficits. All together, these mechanisms are implicated in memory disorders. Objectives: To investigate the histochemical changes in the hippocampus and entorhinal cortex of Wistar rats' offspring after prenatal exposure to mosquito coil smoke and its effect on memory. . Methods: 12 pregnant Wistar rats were grouped into four, 3 animals per group. Group I was exposed to fresh air. Groups II, III, and IV were exposed to mosquito coil smoke for 4, 6 and 8 hours daily respectively throughout gestation period. On Post-natal day (PND) 28 and 29, shortterm spatial and recognition memory of adolescent wistar rats were assessed using water licking task and novel object recognition test respectively. For each animal group (I-IV), a total of 8 animals were randomly selected from the litters for neurobehavioral studies. Experimental animals were humanely sacrificed and sections from the hippocampus and entorhinal cortex were processed for histochemical studies using Bielschowsky stain. Data were presented as mean ± SEM; analysed using One-way analysis of variance and Tukey's Multiple Comparison Test (p<0.05). Results and Conclusion: Our results showed significant impairment in short-term recognition and spatial memory of group III and IV adolescent wistar rats when compared with the control (p<0.05) and the formation of neurofibrillary tangle-like structures in neurons of the studied regions. .

Inhalation Administration of Agarwood Incense Rescues Scopolamine-Induced Learning and Memory Impairment in Mice

Background: Agarwood, a type of herbal medicine widely used in Asian countries, is noted in traditional medicine for its intelligence-enhancing effects. Agarwood incense is traditionally administered by oral and nasal inhalation. To verify whether agarwood incense can exert its intelligence-enhancing effects in this way to rescue learning and memory impairment, typical clinical manifestations of dementia, we conducted a set of behavioral tests related to learning and memory.Methods: C57BL/6 mice were divided into six groups. In addition to the control and model groups, we added a donepezil treatment group to evaluate the effect of three different agarwood administration doses. After a week of administration, scopolamine was injected 30 min before each behavioral test to create a learning and memory impairment model. A series of behavioral tests [the Morris water maze test (MWM), the novel object recognition test (NOR), and the step-down test (SDT)] were used to assess their learning ability, as well as their spatial and recognition memory.Results: After scopolamine injection, the model group showed significant learning and memory impairment (i.e., longer latencies, lower crossing times, and lesser distance travelled in the target quadrant in MWM; a lower recognition index in NOR; and longer latencies and higher error times in SDT). The other four treatment groups all showed improvements in these indicators, and the overall therapeutic effect of agarwood was superior.Conclusion: The inhalation administration of agarwood can significantly improve the learning and memory impairment caused by scopolamine in mice, and the therapeutic effect varied between doses.

Curcumin for Attention Deficit Hyperactivity Disorder: a Behavioral Preliminary Investigation

Background: Curcumin has protective actions in neuropsychiatric disorders. Its mechanism of action is associated with the restoration of catecholaminergic balance, reduction of oxidative/nitrosative stress, protection against inflammation, and neuroprotection. Objective: In a first approach, the study presents an empty review of the potential effect of curcumin on cognitive performance in attention deficit hyperactivity disorder (ADHD).Methods: On a second moment, seeing the scarcity of studies and knowing that ADHD is related to hyperactive and anxious behavior, 20 spontaneously hypertensive Wistar rats (SHR) were divided into groups that received water (1 mg/kg/day), curcumin (50 mg/kg/day), or methylphenidate (1 mg/kg/day) for 42 days. Behavioral tests to assess activity (Open Field test), anxiety and impulsivity (Elevated Plus Maze, and Social Interaction), and memory (Y Maze and Object Recognition Test) were performed. Results: Animals treated with curcumin showed less anxious and hyperactive behavior. Related to the memory, the results can be related to hyperactivity. Conclusion: Thus, the data suggest that the treatments used here can beneficially modulate the anxious and hyperactive behavior of SHR.

Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines

Rationale Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. Objectives In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. Methods AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. Results Using a blood–brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. Conclusions These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies.

Hippocampal Knockout of p300 Affects Learning and Memory in Mice

Aging has been associated with cognitive decline, as seen in various learning and memory processes. Specifically, p300, a lysine acetyltransferase, has been shown to decrease with age, which could have an effect on cognition. In a series of behavioral tests, the effect of the knockout of p300 was studied in mice. In the water T maze test and the object recognition test, the results conveyed that the mice’s learning skills had not been impacted by the knockout of p300. But the water T maze test results further showed that the p300 knockout mice had a decline in their cognitive flexibility to new information. These findings suggest that the knockout of p300 has a negative impact on cognition. We expect that the overexpression of p300 in older mice will restore the cognition that might have been lost with aging.

Neuroprotective effects of thymoquinone against MDMA-induced neurotoxicity

MDMA (3, 4-methylenedioxymethamphetamine) is a psychoactive substance that is associated with neurotoxicity. MDMA exposure to human results in the degeneration of neuronal cells in the hippocampus. Hence, the purpose of this study was to examine the potential of a natural compound known as thymoquinone (TQ) to protect against neuronal damage and memory impairment in rats stimulated by MDMA. The administration of TQ into MDMA-induced neuronal damage rats was carried out in male Sprague Dawley via a 1-week treatment dividing into four groups (n=36, 7-9 per group). The studied groups involved with the treatments comprise i) Control (1 mL/kg saline), ii) MDMA (10 mg/kg MDMA), iii) MDMA+TQ (10 mg/kg MDMA + 40 mg/kg TQ) and iv) TQ control (40 mg/kg TQ). A novel object recognition test (NORT) was carried out to evaluate the memory performance of the rats, followed by a histopathological assessment of the hippocampal dentate gyrus. The histopathology analysis revealed a significant increase in numbers of positive cells by Fluoro-Jade C following the effect of MDMA on neuronal damage (MDMA induced group) compared to control (P<0.05). Next, the TQ treatments observed in MDMA+TQ exhibited a decline in positive cells from Fluoro-Jade C. The index of recognition memory was found to be increased in MDMA+TQ compared to the MDMA alone (P<0.05). This study suggests that the neuronal damage inflicted by MDMA in a rat model has the potential to be treated by TQ.