Investigation of anti-inflammatory compounds from food and plant libraries for use in Alzheimer's disease

In many chronic neurodegenerative diseases including Alzheimer's disease (AD), chronic activation of microglia can be observed. Microglia, the resident macrophages of the central nervous system, are found in increased numbers surrounding senile amyloid plaques which play a central role in the inflammatory cascade. Macrophages were reported to contribute amyloid angiopathy and massive neuronal tissue destruction is also reported due to high macrophage number. It is also evidenced that COX-2-positive macrophages infiltrate into AD brain damage the blood-brain barrier. In autoimmune animal models, these two related cell types, microglia and macrophages were involved in brain pathology in multiple sclerosis and experimental allergic encephalomyelitis. When activated both secrete a variety of cytokines, including interleukin-1, interleukin-6, and tumor necrosis factor as well as reactive oxygen and nitrogen species (ROS/RNS). Since ROS act as signaling molecules in proinflammatory redox-active signal transduction pathways, it is likely that intracellularly acting plant derived antioxidants, including polyphenols, have been shown to scavenge these "signaling" reactive oxygen species, and thus perform in an anti-inflammatory capacity. Also opportunities exist via diet and lifestyle for contributing to chronic inflammation or alternatively exert anti-inflammatory activity.\ud \ud A selection of Chinese medicinal plants and a sample library from the CSIRO including plant and fungal material such as fruit, leaves, stems, roots, tubers, seeds, juice and pulp, as well as food processing co-products or waste material, for example spent grain from brewing, were tested for ability to attenuate NO and TNF-α production, in vitro. The most potent of them was selected by a high through put screening procedure, involving murine microglia and macrophages. Considering the stability of activity during processing stages (patented processing methods of the CSIRO plant and food library), activity on both the cell lines and suppression of both NO and TNF-α without cytotoxicity, C.zeylanicum has been selected as the lead candidate for further chemical analysis. Though a variety of cinnamon species were extensively studied for the anti-oxidant, anti-diabetic, anti-microbial, anticancer and anti-arthritis properties, there was not much evidence in support of anti-inflammatory properties especially relevant to the species C.zeylanicum.\ud \ud We have identified the presence of 9 bioactives in dried powder of C.zeylanicum bark, namely β-caryophyllene, p-cymene, cinnamaldehyde, 2-methoxy cinnamaldehyde, α-amyl cinnamaldehyde, citral, benzyl benzoate, furfural, cinnamyl alcohol. β-caryophyllene, p-cymene, cinnamaldehyde and its derivatives 2-methoxy cinnamaldehyde and α-amyl cinnamaldehyde, citral, benzyl benzoate and furfural have shown both NO and TNF-α inhibitory activity while cinnamyl alcohol and eugenol have shown NO inhibitory activity but not TNF-α inhibition. Neither of these constituents showed significant levels of cytotoxicity at doses inhibiting NO (percentage cell viability <80%), but citral, pcymene and α-amyl cinnamaldehyde showed cell death at IC₅₀ doses of TNF-α inhibition.\ud \ud In conclusion, the compounds β-caryophyllene, cinnamaldehyde, 2-methoxy cinnamaldehyde, benzyl benzoate and furfural may be promising as leads in the development of anti-inflammatory treatments in diseases of pathological inflammation, including AD

Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia. Neuritic amyloid plaques and concomitant chronic inflammation are prominent pathological features of AD. β-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs), post-translational protein modifications, are key activators of plaque-associated inflammation. Aβ, AGEs, S100b, and amphoterin bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB)-regulated cytokines. RAGE-mediated inflammation caused by glial cells and subsequent changes in neuronal glucose metabolism are likely to be important contributors to neurodegeneration in AD. As long as the neuronal damage is reversible, drugs interfering with the Aβ and AGE–RAGE pathways might be interesting novel therapeutics for the treatment of AD

Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia. Neuritic amyloid plaques and concomitant chronic inflammation are prominent pathological features of AD. β-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs), post-translational protein modifications, are key activators of plaque-associated inflammation. Aβ, AGEs, SlOOb, and amphoterin bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-KB)-regulated cytokines. PAGE-mediated inflammation caused by glial cells and subsequent changes in neuronal glucose metabolism are likely to be important contributors to neurodegeneration in AD. As long as the neuronal damage is reversible, drugs interfering with the Ap and AGE-RAGE pathways might be interesting novel therapeutics for the treatment of AD

α-lipoic acid in the treatment of diabetic polyneuropathy and Alzheimer’s disease

α-lipoic acid (LA) is a naturally occurring cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH). LA acts as a powerful micronutrient with diverse pharmacological properties. LA improves glucose uptake and insulin sensitivity, and thus decreases blood glucose levels and increases mitochondrial energy levels. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals from hydrogen peroxide and also scavenges reactive oxygen species, thereby increasing the levels of reduced glutathione. Via the same mechanisms, down-regulation of redox-sensitive inflammatory processes is achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. LA is currently studied for the treatment of some neurodegenerative diseases with diverse pathophysiology, including diabetic polyneuropathy and Alzheimer’s disease. For diabetic polyneuropathy, LA has been used for decades in Germany with a number of clinical trials showing benefits in insulin-stimulated glucose uptake and attenuating symptoms of neuropathy. In Alzheimer’s disease, an open-label trial in patients with mild and moderate Alzheimer’s disease is currently conducted at a at the memory clinic of the Henriettenstiftung hospital in Hannover, Germany. Interim analysis of the data after 4 years show that the progression rate of the patient treated with 600 mg LA daily is significantly slower than to the non-treated control group - particularly in early stages of dementia - and other control groups in published studies

New drugs under development for Alzheimer\u27s disease

Past research has shed light on many of the hidden secrets of Alzheimer’s disease. This has revealed key neurological features, including the deposition of aggregates of insoluble β-amyloid and formation of neurofibrillary tangles, as well as chronic inflammation. These pathological hallmarks of the disease have been assumed to be part of ‘the cause of Alzheimer’s disease’ and were specifically targeted to develop an effective therapeutic approach, to interfere with the pathological cascades in Alzheimer’s disease. This chapter will systematically analyze the current and emerging therapies for this complex neurodegenerative disease. However, due to the limitations of space, combination treatments will not be covered

Determination of anti-inflammatory activities of standardised preparations of plant- and mushroom-based foods

Purpose: Chronic inflammatory processes contribute to the pathogenesis of many age-related diseases. In search of anti-inflammatory foods, we have systematically screened a variety of common dietary plants and mushrooms for their anti-inflammatory activity. Methods: A selection of 115 samples was prepared by a generic food-compatible processing method involving heating. These products were tested for their anti-inflammatory activity in murine N11 microglia and RAW 264.7 macrophages, using nitric oxide (NO) and tumour necrosis factor-α (TNF-α) as pro-inflammatory readouts. Results: Ten food samples including lime zest, English breakfast tea, honey-brown mushroom, button mushroom, oyster mushroom, cinnamon and cloves inhibited NO production in N11 microglia, with IC50 values below 0.5 mg/ml. The most active samples were onion, oregano and red sweet potato, exhibiting IC50 values below 0.1 mg/ml. When these ten food preparations were retested in RAW 264.7 macrophages, they all inhibited NO production similar to the results obtained in N11 microglia. In addition, English breakfast tea leaves, oyster mushroom, onion, cinnamon and button mushroom preparations suppressed TNF-α production, exhibiting IC50 values below 0.5 mg/ml in RAW 264.7 macrophages. Conclusion: In summary, anti-inflammatory activity in these food samples survived ‘cooking’. Provided that individual bioavailability allows active compounds to reach therapeutic levels in target tissues, these foods may be useful in limiting inflammation in a variety of age-related inflammatory diseases. Furthermore, these foods could be a source for the discovery of novel anti-inflammatory drugs

Inflammation in Alzheimer's disease, and prevention with antioxidants and phenolic compounds : what are the most promising candidates?

Early studies of Alzheimer’s disease (AD) revealed key neurological features including the deposition of aggregates of insoluble β-amyloid (Aβ) peptides, the formation of neurofibrillary tangles (NFT), and signs of chronic inflammation. The initial forms of these pathological hallmarks of the disease, including small oligomers of Aβ peptides and the hyperphosphorylated tau which aggregates into NFT, have been assumed to be part of ‘the cause of AD’ and have been specifically targeted to develop an effective monotherapy, but with limited success. In the absence of effective neuroprotective drugs, acetylcholinesterase inhibitors have remained as the drug class that is most used to treat AD, yet they cannot and do not slow the progression of the disease. Imaging studies have confirmed what has long been suspected - that there is a very long pre-clinical phase, when pathology gradually builds up, possibly starting with chronic inflammation, oxidative stress, and dysregulated metabolism. Emerging therapies are targeted more towards these changes, sometimes as well as the Aβ and NFT pathologies in multi-targeted approaches, to interfere with the pathological cascades in AD. The aim is to prevent, stop, or at least slow the neurodegeneration before debilitating symptoms appear. This chapter summarises inflammatory and oxidative stress-related changes that occur in AD, and discusses some emerging therapies and supplements, particularly those directed at inflammation, that may slow pathogenesis of this complex neurodegenerative disease

Induction of novel cytokines and chemokines by advanced glycation endproducts determined with a cytometric bead array

Advanced glycation endproducts (AGEs) accumulate on long-lived protein deposits, e.g. those composed of β2-microglobulin (in dialysis-related amyloidosis) or β-amyloid peptide (in Alzheimer's disease). When AGEs bind to the "receptor for advanced glycation endproducts", they activate redox-sensitive transcription factors such as NF-κB, and subsequently induce the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. Using a cytokine bead array, we have further analyzed the Bovine Serum Albumin (BSA)-AGE induced expression of selected cytokines/chemokines in two murine cell lines, RAW 264.7 macrophages and N-11 microglia. Our study showed that monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF-α) were both released in a time-dependent manner from both RAW 264.7 macrophages and N-11 microglia upon stimulation with BSA-AGE or lipopolysaccharide (LPS), which was used as a positive control. Interestingly, MCP-1 was also constitutively expressed by unstimulated cells, although at a lower levels. Much higher levels of IL-6 were secreted by RAW 264.7 macrophages than by N-11 microglia in response to both stimuli. IL-12p70, interferon-γ and the anti-inflammatory cytokine IL-10 were not induced by either LPS or BSA-AGE. Our results indicate a very similar pattern of chemokine and cytokine expression induced by such different ligands as AGEs and LPS indicating similar or convergent downstream signaling pathways

Novel neuroprotective therapies for Alzheimer's and Parkinsons's disease

One of the major age-related damaging agents are reactive oxygen species (ROS). The brain is more vulnerable to oxidative stress than other organs as concomitant low activity and capacity of antioxidative protection systems allow for increased exposure of target molecules to ROS. Since neurons are postmitotic cells, they have to live with cellular damage accumulated over many decades. Increased levels of ROS (also termed "oxidative stress"), produced by normal mitochondrial activity, inflammation and excess glutamate levels, are proposed to accelerate neurodegenerative processes characteristic for Alzheimer's disease and Parkinson's disease. This review presents evidence for the importance of oxidative stress in the pathogenesis of these diseases and explains the nature of different types of ROS mediating neuronal damage. Furthermore, the potential beneficial effects of neuroprotective treatments, including synthetic and plant deroved antioxidants, energy supplements and anti - glutamatergic drugs are discussed

Determination of anti-inflammatory activities of standardised preparations of plant- and mushroom-based foods

Conclusion: In summary, anti-inflammatory activity in these food samples survived 'cooking'. Provided that individual bioavailability allows active compounds to reach therapeutic levels in target tissues, these foods may be useful in limiting inflammation in a variety of age-related inflammatory diseases. Furthermore, these foods could be a source for the discovery of novel anti-inflammatory drugs.