Curcumin and Heme Oxygenase: Neuroprotection and Beyond.

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin's safety profile have been addressed.

Alzheimer's disease and gut microbiota modifications: The long way between preclinical studies and clinical evidence.

Recent studies have suggested the role of an infectious component in the pathogenesis of Alzheimer's disease (AD). In light of this, research has focused on some bacteria constituting the intestinal microbial flora which can produce amyloid. Once generated, the latter hypothetically triggers a systemic inflammatory response which compromises complex brain functions, such as learning and memory. Clinical studies have shown that, in cognitively impaired elderly patients with brain amyloidosis, there is lower abundance in the gut of E. rectale and B. fragilis, two bacterial species which have an anti-inflammatory activity, versus a greater amount of pro-inflammatory genera such as Escherichia/Shigella. According to these findings, some clinical studies have demonstrated that supplementation with Lactobacilli- and Bifidobacteria- based probiotics has improved cognitive, sensory and emotional functions in subjects with AD. Moreover, certain herbal products, in particular dietetic polyphenols, have proved capable of restoring dysbiosis and, therefore, their prebiotic role could be effective in counteracting the onset of AD regardless of their activity of free radical scavenging or enhancement of the cell stress response. One of the recent greatest novelties in the field of neurodegenerative diseases is the chance to prevent or slow down AD progression with agents, such as probiotics and prebiotics, acting outside the central nervous system.

The contribution of transgenic and nontransgenic animal models in Alzheimer's disease drug research and development.

Over the last few years, several papers have become available in the literature on both the main hallmarks of Alzheimer's disease (AD) and the several intracellular pathways whose alteration is responsible for its onset and progression. The use of transgenic and nontransgenic animal models has played a key role in achieving such a remarkable amount of preclinical data, allowing researchers to dissect the cellular changes occurring in the AD brain. In addition, the huge amount of preclinical evidence arising from these animal models was necessary for the further clinical development of pharmacological agents capable of interfering with most of the impaired neural pathways in AD patients. In this respect, a significant role is played by the dysfunction of excitatory and inhibitory neurotransmission responsible for the cognitive and behavioral symptoms described in AD patients. The aim of this review is to summarize the main animal models that contributed toward unraveling the pathological changes in neurotransmitter synthesis, release, and receptor binding in AD preclinical studies. The review also provides an updated description of the current pharmacological agents - still under clinical development - acting on the neurotransmitter systems.

Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases.

Modulation of endogenous cellular defense mechanisms via the vitagene system represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. The possibility of high-throughoutput screening using proteomic techniques, particularly redox proteomics, provide more comprehensive overview of the interaction of proteins, as well as the interplay among processes involved in neuroprotection. Here by introducing the hormetic dose response concept, the mechanistic foundations and applications to the field of neuroprotection, we discuss the emerging role of heat shock protein as prominent member of vitagene network in neuroprotection and redox proteomics as a tool for investigating redox modulation of stress responsive vitagenes. Hormetic mechanisms are reviewed as possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the neurodegenerative disease process.

Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain.

DS is the most frequent genetic cause of intellectual disability characterized by the anomalous presence of three copies of chromosome 21. One of the peculiar features of DS is the onset of Alzheimer's disease neuropathology after the age of 40years characterized by deposition of senile plaques and neurofibrillary tangles. Growing studies demonstrated that increased oxidative damage, accumulation of unfolded/damaged protein aggregates and dysfunction of intracellular degradative system are key players in neurodegenerative processes. In this study, redox proteomics approach was used to analyze the frontal cortex from DS subjects under the age of 40 compared with age-matched controls, and proteins found to be increasingly carbonylated were identified. Interestingly, our results showed that oxidative damage targets specifically different components of the intracellular quality control system such as GRP78, UCH-L1, V0-ATPase, cathepsin D and GFAP that couples with decreased activity of the proteasome and autophagosome formation observed. We also reported a slight but consistent increase of Aß 1-42 SDS- and PBS-soluble form and tau phosphorylation in DS versus CTR. We suggest that disturbance in the proteostasis network could contribute to the accumulation of protein aggregates, such as amyloid deposits and NFTs, which occur very early in DS. It is likely that a sub-optimal functioning of degradative systems occur in DS neurons, which in turn provide the basis for further accumulation of toxic protein aggregates. The results of this study suggest that oxidation of protein members of the proteostatis network is an early event in DS and might contribute to neurodegenerative phenomena.

The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it's time for reconciliation.

Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.

Panax notoginseng: Pharmacological Aspects and Toxicological Issues.

Current evidence suggests a beneficial role of herbal products in free radical-induced diseases. Panax notoginseng (Burk.) F. H. Chen has long occupied a leading position in traditional Chinese medicine because of the ergogenic, nootropic, and antistress activities, although these properties are also acknowledged in the Western world. The goal of this paper is to review the pharmacological and toxicological properties of P. notoginseng and discuss its potential therapeutic effect. A literature search was carried out on Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials databases. The following search terms were used: "notoginseng", "gut microbiota", "immune system", "inflammation", "cardiovascular system", "central nervous system", "metabolism", "cancer", and "toxicology". Only peer-reviewed articles written in English, with the full text available, have been included. Preclinical evidence has unraveled the P. notoginseng pharmacological effects in immune-inflammatory, cardiovascular, central nervous system, metabolic, and neoplastic diseases by acting on several molecular targets. However, few clinical studies have confirmed the therapeutic properties of P. notoginseng, mainly as an adjuvant in the conventional treatment of cardiovascular disorders. Further clinical studies, which both confirm the efficacy of P. notoginseng in free radical-related diseases and delve into its toxicological aspects, are mandatory to broaden its therapeutic potential.

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.

Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability in children, and the number of adults with DS reaching old age is increasing. By the age of 40 years, virtually all people with DS have sufficient neuropathology for a postmortem diagnosis of Alzheimer disease (AD). Trisomy 21 in DS leads to an overexpression of many proteins, of which at least two are involved in oxidative stress and AD: superoxide dismutase 1 (SOD1) and amyloid precursor protein (APP). In this study, we tested the hypothesis that DS brains with neuropathological hallmarks of AD have more oxidative and nitrosative stress than those with DS but without significant AD pathology, as compared with similarly aged-matched non-DS controls. The frontal cortex was examined in 70 autopsy cases (n=29 control and n=41 DS). By ELISA, we quantified soluble and insoluble Aß40 and Aß42, as well as oligomers. Oxidative and nitrosative stress levels (protein carbonyls, 4-hydroxy-2-trans-nonenal (HNE)-bound proteins, and 3-nitrotyrosine) were measured by slot-blot. We found that soluble and insoluble amyloid beta peptide (Aß) and oligomers increase as a function of age in DS frontal cortex. Of the oxidative stress markers, HNE-bound proteins were increased overall in DS. Protein carbonyls were correlated with Aß40 levels. These results suggest that oxidative damage, but not nitrosative stress, may contribute to the onset and progression of AD pathogenesis in DS. Conceivably, treatment with antioxidants may provide a point of intervention to slow pathological alterations in DS.

Biliverdin as a disease-modifying agent: An integrated viewpoint.

Biliverdin is one of the three by-products of heme oxygenase (HO) activity, the others being ferrous iron and carbon monoxide. Under physiological conditions, once formed in the cell, BV is reduced to bilirubin (BR) by the biliverdin reductase (BVR). However, if BVR is inhibited by either genetic variants, as occurs in the Inuit ethnicity, or dioxin intoxication, BV accumulates in cells giving rise to a clinical syndrome known as green jaundice. Preclinical studies have demonstrated that BV not only has a direct antioxidant effect by scavenging free radicals, but also targets many signal transduction pathways, such as BVR, soluble guanylyl cyclase, and the aryl hydrocarbon receptor. Through these direct and indirect mechanisms, BV has shown beneficial roles in ischemia/reperfusion-related diseases, inflammatory diseases, graft-versus-host disease, viral infections and cancer. Unfortunately, no clinical data are available to confirm these potential therapeutic effects and the kinetics of exogenous BV in humans is unknown. These limitations have so far excluded the possibility of transforming BV from a mere by-product of heme degradation into a disease-modifying agent. A closer collaboration between basic and clinical researchers would be advantageous to overcome these issues and promote translational research on BV in free radical-induced diseases.

The impact of heme oxygenase-2 on pharmacological research: A bibliometric analysis and beyond.

Heme oxygenase (HO-2) is an enzyme mainly involved in the physiologic turnover of heme and intracellular gas sensing, and it is very abundant in the brain, testes, kidneys and vessels. Since 1990, when HO-2 was discovered, the scientific community has underestimated the role of this protein in health and disease, as attested by the small amount of articles published and citations received. One of the reason that have contributed to the lack of interest in HO-2 was the difficulty in upregulating or inhibiting this enzyme. However, over the last 10 years, novel HO-2 agonists and antagonists have been synthesized, and the availability of these pharmacological tools should increase the appeal of HO-2 as drug target. In particular, these agonists and antagonists could help explain some controversial aspects, such as the neuroprotective versus neurotoxic roles of HO-2 in cerebrovascular diseases. Furthermore, the discovery of HO-2 genetic variants and their involvement in Parkinson's disease, in particular in males, opens new avenues for pharmacogenetic studies in gender medicine.

Exploring the Contribution of Curcumin to Cancer Therapy: A Systematic Review of Randomized Controlled Trials.

Although the anticancer role of curcumin has been extensively addressed in preclinical research, only a few studies were carried out in humans, with conflicting results. The aim of this systematic review is to collate together the results of the therapeutic effect of curcumin in cancer patients. A literature search was carried out in Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials up to 29 January 2023. Only randomized controlled trials (RCTs) designed to evaluate the effects of curcumin on cancer progression, patient survival, or surgical/histological response were included. Seven out of 114 articles, published between 2016 and 2022, were analyzed. They evaluated patients with locally advanced and/or metastatic prostate, colorectal, and breast cancers, as well as multiple myeloma and oral leucoplakia. Curcumin was given as an add-on therapy in five studies. Cancer response was the most investigated primary endpoint and curcumin issued some positive results. On the contrary, curcumin was ineffective in improving overall or progression-free survival. The curcumin safety profile was favorable. In conclusion, available clinical evidence is not strong enough to support the therapeutic use of curcumin in cancer. New RCTs exploring the effects of different curcumin formulations in early-stage cancers would be welcome.

Biliverdin reductase--a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment.

Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment.

Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease.

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-A's involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with ß-secretase protein levels in the brain, suggesting a possible role for BVR-A in Aß formation.

Sex differences in brain proteomes of neuron-specific STAT3-null mice after cerebral ischemia/reperfusion.

Signal transduction and activator of transcription-3 (STAT3) plays an important role in neuronal survival, regeneration and repair after brain injury. We previously demonstrated that STAT3 is activated in brain after cerebral ischemia specifically in neurons. The effect was sex-specific and modulated by sex steroids, with higher activation in females than males. In the current study, we used a proteomics approach to identify downstream proteins affected by ischemia in male and female wild-type (WT) and neuron-specific STAT3 knockout (KO) mice. We established four comparison groups based on the transgenic condition and the hemisphere analyzed, respectively. Moreover, the sexual variable was taken into account and male and female animals were analyzed independently. Results support a role for STAT3 in metabolic, synaptic, structural and transcriptional responses to cerebral ischemia, indeed the adaptive response to ischemia/reperfusion injury is delayed in neuronal-specific STAT3 KO mice. The differences observed between males and females emphasize the importance of sex-specific neuronal survival and repair mechanisms, especially those involving antioxidant and energy-related activities, often caused by sex hormones.

Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity.

At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous molecule is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep-wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic.

Atorvastatin treatment in a dog preclinical model of Alzheimer's disease leads to up-regulation of haem oxygenase-1 and is associated with reduced oxidative stress in brain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Only acetylcholinesterase inhibitors and the NMDA antagonist memantine are approved for AD treatment. Recent preclinical and epidemiological studies proposed statins as novel therapeutics for AD, but the mechanisms of action are still unknown. Here, we demonstrate that atorvastatin (80 mg/d for 14.5 months) treatment resulted in an up-regulation of the inducible isoform of haem oxygenase (HO-1), an enzyme with significant neuroprotective activity. Atorvastatin selectively increased HO-1 in the parietal cortex but not cerebellum. In contrast, HO-2 was increased in cerebellum but not parietal cortex. No changes were observed in HO-1 or HO-2 in the liver. Significant negative correlations between HO-1 and oxidative stress indices and positive correlations with glutathione levels in parietal cortex were found. HO-1 up-regulation significantly correlated with lower discrimination learning error scores in aged beagles. Reference to therapeutic applications of atorvastatin in AD is discussed.

The brain heme oxygenase/biliverdin reductase system as a target in drug research and development.

INTRODUCTION: The heme oxygenase/biliverdin reductase (HO/BVR) system is involved in heme metabolism. The inducible isoform of HO (HO-1) and BVR both exert cytoprotective effects by enhancing cell stress response. In this context, some xenobiotics, which target HO-1, including herbal products, behave as neuroprotectants in several experimental models of neurodegeneration. Despite this, no drug having either HO-1 or BVR as a main target is currently available. AREAS COVERED: After a description of the brain HO/BVR system, the paper analyzes the main classes of drugs acting on the nervous system, with HO as second-level target, and their neuroprotective potential. Finally, the difficulties that exist for the development of drugs acting on HO/BVR and the possible ways to overcome these hurdles are examined. EXPERT OPINION: Although the limited clinical evidence has restricted the translational research on the HO/BVR system, mainly because of the dual nature of its by-products, there has been growing interest in the therapeutic potential of these enzymes. Scientists should boost the translational research on the HO/BVR system which could be supported by the significant evidence provided by preclinical studies.

Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders.

Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects in preclinical studies and lack effectiveness in various recent clinical trials. This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with particular emphasis on Alzheimer disease.

Long-term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of Alzheimer disease: a novel mechanism of action.

Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss, inability to perform the activities of daily living and personality changes. Unfortunately, drugs effective for this disease are limited to acetylcholinesterase inhibitors that do not impact disease pathogenesis. Statins, which belong to the class of cholesterol-reducing drugs, were proposed as novel agents useful in AD therapy, but the mechanism underlying their neuroprotective effect is still unknown. In this study, we show that atorvastatin may have antioxidant effects, in aged beagles, that represent a natural higher mammalian model of AD. Atorvastatin (80 mg/day for 14.5 months) significantly reduced lipoperoxidation, protein oxidation and nitration, and increased GSH levels in parietal cortex of aged beagles. This effect was specific for brain because it was not paralleled by a concomitant reduction in all these parameters in serum. In addition, atorvastatin slightly reduced the formation of cholesterol oxidation products in cortex but increased the 7-ketocholesterol/total cholesterol ratio in serum. We also found that increased oxidative damage in the parietal cortex was associated with poorer learning (visual discrimination task). Thus, a novel pharmacological effect of atorvastatin mediated by reducing oxidative damage may be one mechanism underlying benefits of this drug in AD.