phycocyanobilin and Neurodegenerative-Diseases

The edible cyanobacterium Spirulina platensis and its chief biliprotein C-Phycocyanin have shown protective activity in animal models of diverse human health diseases, often reflecting antioxidant and anti-inflammatory effects. The beneficial effects of C-Phycocyanin seem likely to be primarily attributable to its covalently attached chromophore Phycocyanobilin (PCB). Within cells, biliverdin is generated from free heme and it is subsequently reduced to bilirubin. Although bilirubin can function as an oxidant scavenger, its potent antioxidant activity reflects its ability to inactivate some isoforms of NADPH oxidase. Free bilirubin can also function as an agonist for the aryl hydrocarbon receptor (AhR); this may explain its ability to promote protective Treg activity in cellular and rodent models of inflammatory disease. AhR agonists also promote transcription of the gene coding for Nrf-2, and hence can up-regulate phase 2 induction of antioxidant enzymes, such as HO-1. Hence, it is proposed that C-Phycocyanin/PCB chiefly exert their protective effects via inhibition of NADPH oxidase activity, as well as by AhR agonism that both induces Treg activity and up-regulates phase 2 induction. This simple model may explain their potent antioxidant/antiinflammatory effects. Additionally, PCB might mimic biliverdin in activating anti-inflammatory signaling mediated by biliverdin reductase. This essay reviews recent research in which CPhycocyanin and/or PCB, administered orally, parenterally, or intranasally, have achieved marked protective effects in rodent and cell culture models of Ischemic Stroke and Multiple Sclerosis, and suggests that these agents may likewise be protective for Alzheimer's disease, Parkinson's disease, and in COVID-19 and its neurological complications.

Topics: Animals; COVID-19; Dietary Supplements; Humans; Neurodegenerative Diseases; Phycobilins; Phycocyanin; SARS-CoV-2

Naturally occurring T regulatory cells targeting epitopes derived from various heat shock proteins escape thymic negative selection and can be activated by vaccination with heat shock proteins; hence, vaccination with such proteins has exerted favorable effects on rodent models of autoimmune disorders. A more elegant way to achieve such vaccination, first evaluated clinically by Al-Harbi in the early 1990s, is to subject mononuclear cells to survivable heat shock ex vivo, incubate them at physiological temperature for a further 24-48 h, and then inject them subcutaneously; anecdotally, beneficial effects were observed with this strategy in a wide range of autoimmune and inflammatory conditions. There is growing evidence that M1-activated microglia play a primary or secondary role in the pathogenesis of numerous neurodegenerative diseases, as well as in major depression. T regulatory cells, by polarizing microglial toward a reparative M2 phenotype, have the potential to aid control of such disorders. It would be appropriate to test the heat-shocked mononuclear cell vaccination strategy in animal models of neurodegeneration and major depression, and to evaluate this approach clinically if such studies yield encouraging results.

Topics: Heat-Shock Response; Humans; Microglia; Models, Immunological; Neurodegenerative Diseases; Phycobilins; Phycocyanin; T-Lymphocytes, Regulatory; Vaccination

There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age--albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications.

Topics: Administration, Oral; Animals; Brain; Computer Simulation; Humans; Mice; Microglia; Models, Neurological; NADPH Oxidases; Neurodegenerative Diseases; Neuroprotective Agents; Phycobilins; Phycocyanin; Rats; Signal Transduction