Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the . Vinpocetine: Vinpocetine exerts neuroprotective effects in ischaemia of the brain through actions on cation channels, glutamate receptors and. CNS Neurosci Ther. Apr;23(4) doi: /cns The neuroprotective effects of caffeine in neurodegenerative diseases. Kolahdouzan . Int J Dev Neurosci. Jul-Aug;18() Neuroprotective effects of estrogens: potential mechanisms of action. Green PS(1), Simpkins JW.
Curcumin has an outstanding safety profile and a number of pleiotropic actions with potential for neuroprotective efficacy, including anti-inflammatory, antioxidant, and anti-protein-aggregate activities.
These can be achieved at sub-micromolar levels. However, despite concerns about poor oral bioavailability, curcumin has at least 10 known neuroprotective actions and many of these might be realized in vivo. Promising results have already led to ongoing pilot clinical trials.
Many neurodegenerative diseases of aging involve the accumulation of protein aggregates, oxidative damage, and inflammation. Curcumin has multiple desirable characteristics for a neuroprotective drug, including anti-inflammatory, antioxidant, and anti-protein-aggregate activities that we have previously reviewed.
One of the key obstacles with curcumin, as with other compounds lacking adequate patent protection, is that there has been no push for development from the private sector. What is needed is preclinical and clinical development support from either government or philanthropic support. For example, low-nanomolar doses can inhibit histone acetyltransferase 15 and JNK-stimulated AP-1 activity, suggesting that these functions are likely central to many in vivo effects, 16 , 17 including central nervous system CNS neuroprotective activity.
There are millions of AD patients in the United States today and this number is expected to double and double again with the demographic shift toward a more aged population, leading to over 10 million expected cases, unless preventive measures can be achieved. More recently, tangle pathology has been achieved by expressing high levels of mutant human tau or wild-type human tau on a mouse tau knockout background, but curcumin effects have not been reported on in these models. This efficacy in late stages of amyloid deposition is in marked contrast to other antioxidants and other treatments that fail to reduce amyloid in the same Tg model mice when treatments are begun late.
Amyloid formation has been shown to be limited by five additional mechanisms: Iron chelation is another activity that also has in vivo support. Further, high doses of curcumin can also inhibit amyloid toxicity in vitro and neurotoxic p75 neurotrophin receptor signaling.
Tau dimerization is initiated by oxidative damage 53 and at least some tau kinases, notably mitogen-activated protein kinase MAPK , are activated by oxidative damage. Although there is no epidemiology isolating curcumin intake as a variable, age-adjusted AD prevalence and incidence in an area with high curcumin intake rural India was surprisingly low compared to the United States and other Western countries.
Of the age-related neurodegenerative conditions, PD has long had the strongest associations with elevated oxidative damage, including that associated with auto-oxidative dopamine breakdown and related semiquinone metabolism to superoxide, as well as monoamine oxidase production of hydrogen peroxide.
Synuclein aggregates show evidence of nitration-based oxidative damage 62 that might play a critical role in aggregate formation. These diseases have extended C-terminal CAG repeats coding for polyglutamine, which causes protein aggregates to form at a rate determined by the repeat length.
Marie-Charcot Tooth disorder is another example of a similar protein-misfolding neuropathy and curcumin protects against this disorder in vitro 69 and in vivo in a transgenic model Lupski, personal communication. Aggregates of the microtubule-associated protein tau are present in neurofibrillary tangles in AD and tau mutations have been genetically linked to neurodegeneration in some forms of frontotemporal dementia FTD , which can be modeled in FTD mutant tau transgenic mice.
Although an abstract report claimed that curcumin can reduce tau pathology in one of the tau transgenic models, as far as we are aware there are no peer-reviewed publications on this topic. Based on this suggestive data, ongoing studies are further examining the impact of curcumin on tau pathology. Cerebrovascular and cardiovascular disease risk factors overlap AD risk factors and many dementia cases are mixed.
Prior and even delayed curcumin treatment reduces this damage. For example, curcumin injections i. Head trauma is a stringent test of neuroprotective activity and a validated environmental risk factor for AD. Ethanol-induced toxicity involves lipid peroxidation, inflammation, and other well-established curcumin targets.
Not surprisingly, curcumin can effectively protect against ethanol-induced oxidative damage, inflammation, and resulting liver damage 6 and ethanol-induced CNS neurodegeneration in vivo. Curcumin is one of the few drugs likely to slow aging rates, as evidenced by the ability of its major metabolite, tetrahydrocurcumin, to increase the life span in middle-aged mice. These results are intriguing, consistent with other measures of normal brain aging, including protection against CNS oxidative damage, and support the hypothesis that curcumin might slow normal aging of the brain and presumably other tissues in which age-related oxidative damage is an issue.
Although still controversial, adult neurogenesis appears to be both modulatable and therapeutically significant. Curcumin has been reported to stimulate neuronal differentiation of stem cells in vitro and adult neurogenesis in vivo , notably in the striatum. As summarized in Table 1 , curcumin has at least ten neuroprotective effects and it can apparently act at nanomolar or even picomolar doses. Like any drug, it needs preclinical development to establish dosing, formulation, pharmacokinetics, therapeutic windows, and potential toxicity.
Normally, these issues are the concern of drug companies, but in the absence of patent protection, this is unlikely to occur.
Primary prevention of age-related neurodegeneration would be the eventual goal, but this is even less likely to ever be tested in clinical trials. Most chronic age-related conditions are not caused by foreign pathogens, but the failure to repair or resist chronic age-related lesions arising from naturally occurring damage or imbalances. They involve prolonged multistep cascades that induce slow degeneration that would best be dealt with by long-term prevention with very inexpensive and safe interventions rather than new drugs with unknown or unacceptable costs and side-effect profiles.
This is a huge issue because in the absence of a foreign pathogen, most of the targets will involve essential physiological pathways, where major inhibition will predictably lead to sideeffects. With modest efficacy from multiple beneficial activities, a pleiotropic drug like curcumin can be efficacious without side effects.
Further, the original cause might be superseded by subsequent steps in the cascade and no single pathway might be responsible for ongoing degeneration. For example, most of these diseases involve inflammation and oxidative damage, which are known curcumin targets.
There are other likely beneficial effects. Finally, stimulation of neurogenesis might facilitate functional replacement of lost neurons, and curcumin has been reported to stimulate adult neurogenesis. National Center for Biotechnology Information , U. Adv Exp Med Biol. Author manuscript; available in PMC Sep 1. Cole , Bruce Teter , and Sally A. Copyright and License information Disclaimer.
The publisher's final edited version of this article is available at Adv Exp Med Biol. See other articles in PMC that cite the published article. Abstract Neurodegenerative diseases result in the loss of functional neurons and synapses.
Oxidative Damage and Inflammation Of the age-related neurodegenerative conditions, PD has long had the strongest associations with elevated oxidative damage, including that associated with auto-oxidative dopamine breakdown and related semiquinone metabolism to superoxide, as well as monoamine oxidase production of hydrogen peroxide.
Tauopathies Aggregates of the microtubule-associated protein tau are present in neurofibrillary tangles in AD and tau mutations have been genetically linked to neurodegeneration in some forms of frontotemporal dementia FTD , which can be modeled in FTD mutant tau transgenic mice. Open in a separate window. References are reviewed in the text. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration.
Dose escalation of a curcuminoid formulation. Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B-dependent genes. Immediate and delayed treatments with curcumin prevents forebrain ischemia-induced neuronal damage and oxidative insult in the rat hippocampus. Curcumin diferuloyl-methane down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells.
Redox modulation of chromatin remodeling: Impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Thioredoxin reductase is irreversibly modified by curcumin: A novel molecular mechanism for its anticancer activity.
Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Curcumin enhances the polyglutamine-expanded truncated N-terminal huntingtin-induced cell death by promoting proteasomal malfunction. A good education may have other advantages. Research published in the past few years suggests that it can strengthen the brain, making it more resistant to the ravages of old age, and perhaps mitigating the damage that occurs after traumatic brain injury.
Research into the link between education and dementia began in the mids. Some of the early studies produced conflicting results, but overall the evidence suggests that a higher level of educational attainment is associated with both a decreased risk of Alzheimer's disease and the more-common, slower age-related cognitive decline. They also point to racial differences in the beneficial effects of education: It also means that after diagnosis, they are likely to die sooner.
Level of education may also accurately predict the extent to which one will recover following traumatic brain injury TBI. Researchers from Johns Hopkins Medical School in Baltimore tracked the progress of nearly patients, all of whom had been admitted for rehabilitation after moderate to severe TBI, and had at least one year of follow-up examinations.
This, the researchers conclude, "indicate[s] a robust association between educational attainment and functional recovery… after TBI. Many researchers explain findings such as these in terms of cognitive reserve , a concept that stems from the many observations that some people can continue to function normally despite brain pathology.
The term 'cognitive reserve' was first used in a study , in which researchers from the University of California, San Diego examined the brains of nursing home residents, all of whom had undergone neuropsychological testing before they died.
While 10 of them had remained cognitively healthy-and had outperformed healthy individuals on the tests-post-mortem examination revealed in their brains the pathological changes associated with Alzheimer's. These women also had heavier brains and more neurons than both the demented and healthy residents included in the study, leading the researchers to hypothesize that these extra cells provided a 'reserve' that made them better at coping with the damage caused by the disease.
The idea is that there is a threshold at which deficits become apparent, and those with more reserve need more damage to reach it.
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Neuroprotective approaches work best prior to the initiation of damage, .. As summarized in Table 1, curcumin has at least ten neuroprotective effects and it. Neuroprotective effects of seaweeds against 6-hydroxidopamine-induced cell death on an in vitro human neuroblastoma model. Joana Silva. This study aims to investigate the neuroprotective effects of quercetin in an experimental radiation-induced brain injury. A total of 32 adult male.