Role of melatonin in Alzheimer's disease: From preclinical studies to novel melatonin-based therapies.

Melatonin and novel melatonin-based therapies such as melatonin-containing hybrid molecules, melatonin analogues, and melatonin derivatives have been investigated as potential therapeutics against Alzheimer's disease (AD) pathogenesis. In this review, we examine the developmental trends of melatonin therapies for AD from 1997 to 2021. We then highlight the neuroprotective mechanisms of melatonin therapy derived from preclinical studies. These mechanisms include the alleviation of amyloid-related burden, neurofibrillary tangle accumulation, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and impaired neuroplasticity and neurotransmission. We further illustrate the beneficial effects of melatonin on behavior in animal models of AD. Next, we discuss the clinical effects of melatonin on sleep, cognition, behavior, psychiatric symptoms, electroencephalography findings, and molecular biomarkers in patients with mild cognitive impairment and AD. We then explore the effectiveness of novel melatonin-based therapies. Lastly, we discuss the limitations of current melatonin therapies for AD and suggest two emerging research themes for future study.

Hericium erinaceus Promotes Anti-Inflammatory Effects and Regulation of Metabolites in an Animal Model of Cerebellar Ataxia.

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although previous study demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), the mechanisms of H.E. treatment on the neuroinflammatory response, neurotransmission, and related metabolites remain largely unknown. We demonstrated that 3-AP rats treated with 25 mg/kg H.E. extracts had improved motor coordination and balance in the accelerated rotarod and rod tests. We showed that the H.E. treatment upregulated the expression of Tgfb1, Tgfb2, and Smad3 genes to levels comparable to those in the non-3-AP control group. Interestingly, we also observed a significant correlation between Tgfb2 gene expression and rod test performance in the 3-AP saline group, but not in the non-3-AP control or H.E.+3-AP groups, indicating a relationship between Tgfb2 gene expression and motor balance in the 3-AP rat model. Additionally, we also found that the H.E. treatment increased mitochondrial COX-IV protein expression and normalized dopamine-serotonin neurotransmission and metabolite levels in the cerebellum of the H.E.+3-AP group compared to the 3-AP saline group. In conclusion, our findings suggest that the H.E. treatment improved motor function in the 3-AP rat model, which was potentially mediated through neuroprotective mechanisms involving TGFB2-Smad3 signaling via normalization of neurotransmission and metabolic pathways.

Chronic intermittent hypoxia alters the dendritic mitochondrial structure and activity in the pre-Bötzinger complex of rats.

Mitochondrial bioenergetics is dynamically coupled with neuronal activities, which are altered by hypoxia-induced respiratory neuroplasticity. Here we report structural features of postsynaptic mitochondria in the pre-Bötzinger complex (pre-BötC) of rats treated with chronic intermittent hypoxia (CIH) simulating a severe condition of obstructive sleep apnea. The subcellular changes in dendritic mitochondria and histochemistry of cytochrome c oxidase (CO) activity were examined in pre-BötC neurons localized by immunoreactivity of neurokinin 1 receptors. Assays of mitochondrial electron transport chain (ETC) complex I, IV, V activities, and membrane potential were performed in the ventrolateral medulla containing the pre-BötC region. We found significant decreases in the mean length and area of dendritic mitochondria in the pre-BötC of CIH rats, when compared to the normoxic control and hypoxic group with daily acute intermittent hypoxia (dAIH) that evokes robust synaptic plasticity. Notably, these morphological alterations were mainly observed in the mitochondria in close proximity to the synapses. In addition, the proportion of mitochondria presented with enlarged compartments and filamentous cytoskeletal elements in the CIH group was less than the control and dAIH groups. Intriguingly, these distinct characteristics of structural adaptability were observed in the mitochondria within spatially restricted dendritic spines. Furthermore, the proportion of moderately to darkly CO-reactive mitochondria was reduced in the CIH group, indicating reduced mitochondrial activity. Consistently, mitochondrial ETC enzyme activities and membrane potential were lowered in the CIH group. These findings suggest that hypoxia-induced respiratory plasticity was characterized by spatially confined mitochondrial alterations within postsynaptic spines in the pre-BötC neurons. In contrast to the robust plasticity evoked by dAIH preconditioning, a severe CIH challenge may weaken the local mitochondrial bioenergetics that the fuel postsynaptic activities of the respiratory motor drive.

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Regulation of Melatonin and Neurotransmission in Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.

Therapeutic Potential of Hericium erinaceus for Depressive Disorder.

Depression is a common and severe neuropsychiatric disorder that is one of the leading causes of global disease burden. Although various anti-depressants are currently available, their efficacies are barely adequate and many have side effects. Hericium erinaceus, also known as Lion's mane mushroom, has been shown to have various health benefits, including antioxidative, antidiabetic, anticancer, anti-inflammatory, antimicrobial, antihyperglycemic, and hypolipidemic effects. It has been used to treat cognitive impairment, Parkinson's disease, and Alzheimer's disease. Bioactive compounds extracted from the mycelia and fruiting bodies of H. erinaceus have been found to promote the expression of neurotrophic factors that are associated with cell proliferation such as nerve growth factors. Although antidepressant effects of H. erinaceus have not been validated and compared to the conventional antidepressants, based on the neurotrophic and neurogenic pathophysiology of depression, H. erinaceus may be a potential alternative medicine for the treatment of depression. This article critically reviews the current literature on the potential benefits of H. erinaceus as a treatment for depressive disorder as well as its mechanisms underlying the antidepressant-like activities.

Melatonin Attenuates Pulmonary Hypertension in Chronically Hypoxic Rats.

Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We examined the hypothesis that daily administration of melatonin (10 mg/kg) mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. The right ventricular systolic pressure (RVSP) and the thickness of pulmonary arteriolar wall were measured from normoxic control, vehicle- and melatonin-treated hypoxic rats exposed to 10% O2 for 14 days. Levels of markers for oxidative stress (malondialdhyde) and inflammation (tumor necrosis factor-α (TNFα), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2)) and the expressions of total endothelial NO synthase (eNOS) and phosphorylated eNOS at serine1177 (ser1177) were determined in the lung tissue. We found that the RVSP and the thickness of the arteriolar wall were significantly increased in the vehicle-treated hypoxic animals with elevated levels of malondialdhyde and mRNA expressions of the inflammatory mediators, when compared with the normoxic control. In addition, the phosphorylated eNOS (ser1177) level was significantly decreased, despite an increased eNOS expression in the vehicle-treated hypoxic group. Melatonin treatment significantly attenuated the levels of RVSP, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the eNOS phosphorylation in the lung. These results suggest that melatonin attenuates pulmonary hypertension by antagonizing the oxidative injury and restoration of NO production.

Cardioprotective effects of melatonin against myocardial injuries induced by chronic intermittent hypoxia in rats.

Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH-induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca(2+) homeostasis, and ischemia/reperfusion (I/R)-induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin-treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF-α, IL-6, and COX-2) and fibrotic markers (PC1 and TGF-ß) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin-treated group. Moreover, melatonin treatment mitigated the SR-Ca(2+) homeostasis in the cardiomyocyte during I/R with (i) Ca(2+) overloading, (ii) decreased SR-Ca(2+) content, (iii) lowered expression and activity of Ca(2+) -handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS(ser1177). Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH-induced myocardial inflammation and fibrosis with impaired SR-Ca(2+) handling and exacerbated I/R injury.

Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD. DATA SOURCE: We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. RESULTS: The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor gamma expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy. CONCLUSION: Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

Upregulation of a local renin-angiotensin system in the rat carotid body during chronic intermittent hypoxia.

The carotid body (CB) plays an important role in the alteration of cardiorespiratory activity in chronic intermittent hypoxia (IH) associated with sleep-disordered breathing, which may be mediated by local expression of the renin-angiotensin system (RAS). We hypothesized a pathogenic role for IH-induced RAS expression in the CB. The CB expression of RAS components was examined in rats exposed to IH resembling a severe sleep-apnoeic condition for 7 days. In situ hybridization showed an elevated expression of angiotensinogen in the CB glomus cells in the hypoxic group when compared with the normoxic control group. Immunohistochemical studies and Western blot analysis revealed increases in the protein level of both angiotensinogen and angiotensin II type 1 (AT1) receptors in the hypoxic group, which were localized to the glomic clusters containing tyrosine hydroxylase. RT-PCR studies confirmed that levels of the mRNA expression of angiotensinogen, angiotensin-converting enzyme, AT1a and AT2 receptors were significantly increased in the CBs of the hypoxic rats. Functionally, the [Ca(2+)]i response to exogenous angiotensin II was enhanced in fura-2-loaded glomus cells dissociated from hypoxic rats when compared with those of the normoxic control animals. Pretreatment with losartan, but not PD123319, abolished the angiotensin II-induced [Ca(2+)]i response, suggesting an involvement of AT1 receptors. Moreover, daily treatment of the IH group of rats with losartan attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, the upregulated local RAS expression could play a pathogenic role in the augmented CB activity and local inflammation via AT1 receptor activation during IH conditions in patients with sleep-disordered breathing.

Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways.

PURPOSE: To investigate the protective mechanisms of an 85 % pure extract of (-) epigallocatechin gallate (EGCG) in the development of fibrosis, oxidative stress and inflammation in a recently developed dietary-induced animal model of non-alcoholic fatty liver disease (NAFLD). METHODS: Female Sprague-Dawley rats were fed with either normal rat diet or high-fat diet for 8 weeks to develop NAFLD. For both treatments, rats were treated with or without EGCG (50 mg/kg, i.p. injection, 3 times per week). At the end, blood and liver tissue samples were obtained for histology, molecular, and biochemical analyses. RESULTS: Non-alcoholic fatty liver disease (NAFLD) rats showed significant amount of fatty infiltration, necrosis, fibrosis, and inflammation. This was accompanied by a significant expressional increase in markers for fibrosis, oxidative stress, and inflammation. TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways were also activated. Treatment with EGCG improved hepatic histology (decreased number of fatty score, necrosis, and inflammatory foci), reduced liver injury (from ~0.5 to ~0.3 of ALT/AST ratio), attenuated hepatic changes including fibrosis (reduction in Sirius Red and synaptophysin-positive stain) with down-regulation in the expressions of key pathological oxidative (e.g. nitrotyrosine formation) and pro-inflammatory markers (e.g. iNOS, COX-2, and TNF-α). EGCG treatment also counteracted the activity of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Treatment with EGCG did not affect the healthy rats. CONCLUSIONS: Epigallocatechin gallate (EGCG) reduced the severity of liver injury in an experimental model of NAFLD associated with lower concentration of pro-fibrogenic, oxidative stress, and pro-inflammatory mediators partly through modulating the activities of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Therefore, green tea polyphenols and EGCG are useful supplements in the prevention of NAFLD.

Pathogenic roles of the carotid body inflammation in sleep apnea.

Breathing difficulties in sleep are a hallmark of sleep-disordered breathing commonly observed in patients with sleep disorders. The pathophysiology of sleep apnea is in part due to an augmented activity of the carotid body chemoreflex. Arterial chemoreceptors in the carotid body are sensitive to inflammatory cytokines and immunogenic molecules in the circulation, because cytokine receptors are expressed in the carotid body in experimental animals and human. Intriguingly, proinflammatory cytokines are also locally produced and released in the carotid body. Also, there are significant increases in the expression of proinflammatory cytokines, cytokine receptors, and inflammatory mediators in the carotid body under hypoxic conditions, suggesting an inflammatory response of the carotid body. These upregulated cytokine signaling pathways could enhance the carotid chemoreceptor activity, leading to an overactivity of the chemoreflex adversely effecting breathing instability and autonomic imbalance. This review aims to summarize findings of the literature relevant to inflammation in the carotid body, with highlights on the pathophysiological impact in sleep apnea. It is concluded that local inflammation in the carotid body plays a pathogenic role in sleep apnea, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.

Melatonin attenuates intermittent hypoxia-induced lipid peroxidation and local inflammation in rat adrenal medulla.

Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague-Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome.

Mechanisms of maladaptive responses of peripheral chemoreceptors to intermittent hypoxia in sleep-disordered breathing.

Peripheral chemoreceptors in the carotid body play important roles in the transduction of chemical stimuli in the arterial blood to the central for eliciting the chemoreflex, which mediates the ventilatory and circulatory responses to hypoxia. The activity of carotid chemoreceptor is modulated and significantly contributes to the ventilatory acclimatization at high altitude. In addition, the carotid chemoreceptor activity is augmented in patients with sleep-disordered breathing, notably in central or obstructive sleep apnea, and also in experimental animals. Thus, the carotid body functions to maintain the oxygen homeostasis, whereas anomalous carotid chemoreceptor activities could be both adaptive and pathogenic in sleep apnea. This review aims to summarize the cellular and molecular mechanisms that could mediate the augmented chemoreceptor activity induced by intermittent hypoxia. Our recent findings suggest a pathogenic role of inflammation mediated by an upregulation of renin-angiotensin system in the carotid body in the over-activity of the chemoreflex. These locally regulated mechanisms are proposed to be a significant part of the hypoxia-mediated maladaptive changes of the carotid body function, which could play a role in the pathophysiology of sleep apnea.

Melatonin ameliorates endothelial dysfunction, vascular inflammation, and systemic hypertension in rats with chronic intermittent hypoxia.

The pathogenesis of hypertension in patients with obstructive sleep apnea (OSA) is associated with endothelial dysfunction induced by chronic intermittent hypoxia (IH). Studies have shown that administration of melatonin ameliorates oxidative injury and inflammation. This study examined the effect of melatonin on the oxidative stress, endothelial dysfunction, and inflammation during the pathogenesis of hypertension in chronic IH. Adult Sprague-Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH treatment mimicking a severe OSA condition for 14-21 days. Systolic pressure was significantly higher in the vehicle-treated (144 ± 2.7 mmHg) but not in the melatonin-treated rats (123 ± 5.1 mmHg) by 21-day IH treatment when compared with the normoxic control. Levels of malondialdehyde and the expressions of NADPH oxidase, pro-inflammatory mediators (TNF-α, inducible NO synthase, COX-2), and adhesion molecules (ICAM-1, VCAM-1, and E-selectin) of the thoracic aorta were markedly increased by 14-day IH treatment preceding the hypertensive response. Also, levels of nitric oxide (NO˙), endothelial-dependent relaxation, and the expressions of endothelial NO synthase (eNOS) and antioxidant enzymes (GPx, CAT, and Cu/Zn SOD) were significantly lowered in the IH rats. Melatonin treatment significantly mitigated the increased expression of NADPH oxidase, pro-inflammatory mediators, and adhesion molecules. Moreover, melatonin prevented the endothelial dysfunction with ameliorated levels of NO˙, endothelial-dependent relaxation, and expressions of eNOS and antioxidant enzymes. These results suggest that melatonin is protective against IH-induced hypertension and endothelial dysfunction via an antioxidant and anti-inflammatory mechanism.

Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model.

PURPOSE: To investigate the hepato-protective properties and underlying mechanisms of SAMC in a non-alcoholic fatty liver disease (NAFLD) rat model. METHODS: Female rats were fed with a diet comprising highly unsaturated fat diet (30% fish oil) for 8 weeks to develop NAFLD with or without an intraperitoneal injection of 200 mg/kg SAMC three times per week. After euthanasia, blood and liver samples of rats were collected for histological and biochemical analyses. RESULTS: Co-treatment of SAMC attenuated NAFLD-induced liver injury, fat accumulation, collagen formation and free fatty acids (FFAs). At the molecular level, SAMC decreased the lipogenesis marker and restored the lipolysis marker. SAMC also reduced the expression levels of pro-fibrogenic factors and diminished liver oxidative stress partly through the inhibition in the activity of cytochrome P450 2E1-dependent pathway. NAFLD-induced inflammation was also partially mitigated by SAMC treatment via reduction in the pro-inflammatory mediators, chemokines and suppressor of cytokine signaling. The protective effect of SAMC is also shown partly through the restoration of altered phosphorylation status of FFAs-dependent MAP kinase pathways and diminished in the nuclear transcription factors (NF-κB and AP-1) activity during NAFLD development. CONCLUSIONS: SAMC is a novel hepato-protective agent against NAFLD caused by abnormal liver functions. Garlic or garlic derivatives could be considered as a potent food supplement in the prevention of fatty liver disease.

Therapeutic approaches to non-alcoholic fatty liver disease: past achievements and future challenges.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver injury and mortality in Western countries and China. However, as to date, there is no direct and effective therapy for this disease. The aim of this review is to analyze the key progress and challenges of main current therapeutic approaches in NAFLD. DATA SOURCE: We carried out a PubMed search of English-language articles relevant to NAFLD therapy. RESULTS: There are two major therapeutic strategies for NAFLD treatment: (1) lifestyle interventions (including weight reduction, dietary modification and physical exercise) and (2) pharmaceutical therapies. Lifestyle interventions, particularly chronic and moderate intensity exercise, are the most effective and recognized clinical therapies for NAFLD. For pharmaceutical therapies, although their effects and mechanisms have been extensively investigated in laboratory studies, they still need further tests and investigations in clinical human trials. CONCLUSION: Future advancement of NAFLD therapy should focus on the mechanistic studies on cell based and animal models and human clinical trials of exercise, as well as the combination of lifestyle intervention and pharmaceutical therapy specifically targeting main signaling pathways related to lipid metabolism, oxidative stress and inflammation.

Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms.

Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia.

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways.

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91(phox) and p22(phox)) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1ß and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca(2+)](i)) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca(2+)](i) response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions.

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice.

PURPOSE: To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model. METHODS: Mice were intraperitoneally injected with CCl4 (50 µl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity. RESULTS: SAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels. CONCLUSIONS: Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage.