Neuroprotective effect of low-dose paracetamol treatment against cognitive dysfunction in d-galactose-induced aging mice.

Background: Aging is closely associated to several deleterious conditions and cognitive impairment. Administration of low-dose paracetamol (APAP) has previously been reported to improve cognitive performance in both human and animal studies. However, the altered cognitive effects of low-dose APAP treatment in the aging brain have not been elucidated. Objectives: The purpose of this study was to determine whether low-dose APAP treatment improves cognitive dysfunction in a d-galactose (d-gal)-induced aging model. Materials and methods: APAP (15 and 50 mg/kg p.o.) and vitamin E (Vit E 100 mg/kg p.o.) were administered once daily to d-gal-injected mice (200 mg/kg s.c.) for 6 weeks. The elevated plus maze (EPM), open field, novel object recognition (NOR), and Morris water maze (MWM) tests, respectively, were used to measure altered neurobehavioral functions, including anxiety-like behavior and exploratory locomotor activity, as well as learning and memory performance. The gene transcription of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in brain tissues was evaluated by real-time polymerase chain reaction. Results: Compared to the control, d-gal significantly decreased exploratory locomotor activity and NOR and MWM performance but did not significantly change the activity in the EPM test. However, APAP50 and Vit E significantly reversed the effects of d-gal injection on exploratory locomotor activity. In addition, low-dose APAP (15 and 50 mg/kg) and Vit E significantly improved the reduction in NOR and MWM performance induced by d-gal. Real-time polymerase chain reaction analysis revealed that the mRNA expression of BDNF, neurotrophic tyrosine receptor kinase (NTRK), which is the gene coding TrkB receptor, and cAMP response element-binding protein (CREB) was significantly decreased in the frontal cortex and hippocampus of the d-gal mice. However, APAP50 and Vit E significantly increased BDNF and NTRK mRNA expression in both the frontal cortex and the hippocampus. A lower dose of APAP (15 mg/kg) significantly elevated the mRNA expression of NTRK, but only in the hippocampus. Moreover, APAP50 significantly increased CREB mRNA expression in the frontal cortex and hippocampus. Conclusion: Low-dose APAP treatment has a neuroprotective effect on cognitive dysfunction in the d-gal aging model, and the underlying molecular mechanisms depend on the activation of BDNF/TrkB signaling.

Compulsive-like eating of high-fat high-sugar food is associated with 'addiction-like' glutamatergic dysfunction in obesity prone rats.

Chronic overeating is a core feature of diet-induced obesity. There is increasing evidence that in vulnerable individuals, such overeating could become compulsive, resembling an addictive disorder. The transition to compulsive substance use has been linked with changes at glutamatergic synapses in the nucleus accumbens. In this study, we investigated a potential link between such glutamatergic dysregulation and compulsive-like eating using a rat model of diet-induced obesity. A conditioned suppression task demonstrated that diet-induced obese rats display eating despite negative consequences, as their consumption was insensitive to an aversive cue. Moreover, nucleus accumbens expression of GluA1 and xCT proteins was upregulated in diet-induced obese animals. Lastly, both a computed 'addiction score' (based on performance across three criteria) and weight gain were positively correlated with changes in GluA1 and xCT expression in the nucleus accumbens. These data demonstrate that the propensity for diet-induced obesity is associated with compulsive-like eating of highly palatable food and is accompanied by 'addiction-like' glutamatergic dysregulation in the nucleus accumbens, thus providing neurobiological evidence of addiction-like pathology in this model of obesity.

The Effects of Exercise on Aging-Induced Exaggerated Cytokine Responses: An Interdisciplinary Discussion.

Aging is generally known to be associated with dynamic biological changes, physiological dysfunction, and environmental and psychological decline. Several studies have suggested that aging is associated with increased inflammatory cytokines, causing several diseases. However, the effect of exercise on aging has been less delineated, and the relationships between cytokine activation, aging, and exercise also need further study. Here, we discuss some ideas about the effect of exercise on aging-induced exaggerated cytokine responses and discuss the possible roles of the aging-induced exaggerated cytokine response following exercise. Evidence from these findings suggests that exercise is a beneficially applicable model to use in studies on the mechanisms underlying the age-associated gradated cytokine response, and these results may provide guidelines for health professionals with diverse backgrounds.

Alterations in Synaptic Plasticity and Oxidative Stress Following Long-Term Paracetamol Treatment in Rat Brain.

Several studies have recently revealed that cognitive function can be affected by paracetamol (APAP) treatment. However, the exact impact of this drug treatment on learning and memory has not been clarified. This study aimed to investigate the effect of APAP treatment on the alteration of synapses and oxidative stress in the rat frontal cortex and hippocampus. APAP at a dose of 200 mg/kg bw was fed to adult male Wistar rats through either acute (n = 10), 15-day (n = 10), or 30-day (n = 10) treatment regimens. The synaptic ultrastructure and proteins, synaptophysin (SYP) and postsynaptic density-95 (PSD-95), were monitored. The amount of protein carbonyl oxidation (PCO) and glutathione (GSH) levels were examined. Our results demonstrated that acute treatment with APAP had no effect on synapses and oxidative stress. However, the synapses obtained from rats with 15-day APAP treatment showed a marked shortening of active zones and widening of the synaptic cleft. Decrement of SYP and PSD-95 proteins were demonstrated in these rats as well. With 30-day APAP treatment, the alteration of the synaptic ultrastructure and proteins was more evident. Moreover, the depletion of GSH and the elevation of PCO levels were demonstrated in the rats treated with APAP for 30 days. These results suggest that long-term APAP treatment can induce synaptic degeneration in the hippocampus and frontal cortex. The increase in oxidative stress in these brain areas may be due to the deleterious effect of this drug.

Neuroprotective effect of Asparagus racemosus root extract via the enhancement of brain-derived neurotrophic factor and estrogen receptor in ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Asparagus racemosus (AR) is well known as an Ayurvedic rasayana which used traditionally by Ayurvedic practitioners for nervous disorders and prevent aging. In our previous study it was found that ethanol AR root extract can improve learning and memory impairment, induced by an ovariectomy, but the extract's mechanisms as a neuroprotective property are still unknown. AIM OF THE STUDY: This study aimed to examine the effects and mechanisms of ethanol AR root extract on the alteration of brain-derived neurotrophic factor (BDNF) and estrogen receptor (ER) subtypes in ovariectomized (OVX) rats. MATERIALS AND METHODS: Adult female Wistar rats were divided into five groups, 4 groups underwent ovariectomy, and one group was designed to be the sham control group. Two groups were gavaged with propylene glycol for sham, and a second group similarly prepared for OVX. Two further groups of OVX rats were gavaged once daily, one group with 100 mg/kg b.w. of ethanol AR root extract and the second group with 1000 mg/kg b.w. of ethanol AR root extract. The fifth group was gavaged once daily with 0.1 mg/kg b.w. of 17α-ethynylestradiol (EE). BDNF, ERα and ERß expression were evaluated by western blot analysis. RESULTS: The western blot analysis revealed that the OVX rats showed a significant decrease in BDNF and a down-regulation of ERα and ERß in the frontal cortex and hippocampus. It was also demonstrated that EE and AR root extract increased BDNF, ERα and ERß in the frontal cortex and hippocampus of ovariectomized rats. CONCLUSIONS: Based on these results, the enhancement of BDNF and ERs up-regulation may be involved in the neuroprotective effects of ethanol AR root extract in ovariectomized rat.

Upregulation of Pro-inflammatory Cytokine Expression Following Chronic Paracetamol Treatment in Astrocyte.

The present study aimed to investigate the effect of APAP treatment on the expression of pro-inflammatory cytokines in the astrocytes. The mouse astrocyte cells (C8-D1A) were treated with APAP at the concentration of 100 µM for 24 h, 16 and 28 days. The expressions of pro-inflammatory cytokines and NF-kB were determined using western blot analysis. Furthermore, the expression and localization of phosphorylation of NF-kB were detected by immunohistochemical and immunofluorescent analysis. The ultrastructure of C8-D1A cells was as well monitored. The results revealed that acute APAP treatment (24 h) had no effect on the expression of pro-inflammatory cytokines and pNF-kB. This treatment did not alter the ultrastructure of C8-D1A cells when compared with those in the control cells. However, the results obtained from the study on chronic APAP-treated cells (16 and 28 days) showed the different effect of APAP treatment. The results obtained from western blot analysis showed the increment of pro-inflammatory cytokine (IL-1ß and TNF-α) expressions and the activation of NF-kB signaling pathway. Nuclear translocation of pNF-kB and alteration of several cell structures were well observed in the C8-D1A cells with chronic APAP treatment. The results obtained from this study suggest that chronic APAP treatment can induce an upregulation of pro-inflammatory cytokines (IL-1ß and TNFα) in astrocytes. This alteration implies the involvement of the activation of NF-kB signaling pathway.