More on oxidative stress in neurodegenerative diseases

Glaucoma is a neurodegenerative disease of the optic nerve. Neuroprotection should be of great interest to any glaucoma patient. The abstracts below deal with potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders.

Calabrese V, Cornelius C, Mancuso C, et al:

Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity.

Neurochem Res 2008

The predominant molecular symptom of aging is the accumulation of altered
gene products. Moreover, several conditions including protein, lipid or
glucose oxidation disrupt redox homeostasis and lead to accumulation of
unfolded or misfolded proteins in the aging brain. Alzheimer's and
Parkinson's diseases or Friedreich ataxia are neurological diseases sharing,
as a common denominator, production of abnormal proteins, mitochondrial
dysfunction and oxidative stress, which contribute to the pathogenesis of
these so called "protein conformational diseases". The central nervous
system has evolved the conserved mechanism of unfolded protein response to
cope with the accumulation of misfolded proteins. As one of the main
intracellular redox systems involved in neuroprotection, the vitagene system
is emerging as a neurohormetic potential target for novel cytoprotective
interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp)
Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins.
Nutritional studies show that ageing in animals can be significantly
influenced by dietary restriction. Thus, the impact of dietary factors on
health and longevity is an increasingly appreciated area of research.
Reducing energy intake by controlled caloric restriction or intermittent
fasting increases lifespan and protects various tissues against disease.
Genetics has revealed that ageing may be controlled by changes in
intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked
to aging, metabolism and stress tolerance in several organisms. Recent
findings suggest that several phytochemicals exhibit biphasic dose responses
on cells with low doses activating signaling pathways that result in
increased expression of vitagenes encoding survival proteins, as in the case
of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1
activated by resveratrol. Consistently, the neuroprotective roles of dietary
antioxidants including curcumin, acetyl-L: -carnitine and carnosine have
been demonstrated through the activation of these redox-sensitive
intracellular pathways. Although the notion that stress proteins are
neuroprotective is broadly accepted, still much work needs to be done in
order to associate neuroprotection with specific pattern of stress
responses. In this review the importance of vitagenes in the cellular stress
response and the potential use of dietary antioxidants in the prevention and
treatment of neurodegenerative disorders is discussed.

 

Earlier related work:

V. Calabrese1, G. Scapagnini1, C. Colombrita1, A. Ravagna1, G. Pennisi2, A. M. Giuffrida Stella1, F. Galli3 and D. A. Butterfield4
(1)     Department of Chemistry, Section of Biochemistry and Molecular Biology, Faculty of Medicine, University of Catania, Catania, Italy, IT
(2)     Department of Neurological Sciences, Faculty of Medicine, University of Catania, Catania, Italy, IT
(3)     Section of Clinical Biochemistry, DI.M.I., University of Perugia, Perugia, Italy, IT
(4)     Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, U.S.A., US

Received: 10 October 2003  Revised: 1 January 2003  Accepted: 21 October 2003  Published online: 7 November 2003

Summary.   Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimerrsquos disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis.

Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress.

Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction occurs together with the induction of other HSPs during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response.

Increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimerrsquos disease, in fact, involves a chronic inflammatory response associated with both brain injury and beta-amyloid associated pathology. All of the above evidence suggests that stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as an antidegenerative mechanism potentially important in AD pathogenesis. These findings have offered new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes, such as the HO gene, conceivably may delay the aging process and decrease the occurrence of age-related neurodegenerative diseases.