Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 8: 803-808

Burnham Institute for Medical Research, The Salk Institute for Biological Studies, The Scripps Research Institute, and the University of California at San Diego 10901 North Torrey Pines Road, La Jolla, California 29,037, USA.
Nature Reviews Neuroscience (Impact Factor: 31.43). 11/2007; 8(10):803-8. DOI: 10.1038/nrn2229
Source: PubMed


Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist.

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    • "Over - stimulation of NMDA receptors may produce an excessive Ca 2+ influx that can generate ROS and activate excitotoxicity processes that lead to cell death . Moreover , this excitotoxicity that has been suggested as a mediator of neurotoxicity in this neurodegenerative disorder ( Lipton , 2007a ) , and specifically in neurons , may also activate nNOS and induce NO overproduction ( Gu et al . , 2010 ; Figure 3 ) . "
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    ABSTRACT: Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.
    Frontiers in Cellular Neuroscience 08/2015; 9(322). DOI:10.3389/fncel.2015.00322 · 4.29 Impact Factor
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    • "Furthermore, it was recently showed that compounds with hydroquinone and catechol moieties may be novel cytoprotective agents based on their ability to activate the Keap1/Nrf2/ARE pathway (Satoh et al. 2009). Noteworthy , these molecules have the advantage that their action is sustained and amplified by transcription-mediated signalling pathways (Satoh and Lipton 2007). Since hydroquinones and catechols are not electrophilic may be viewed as pro-drugs (Bensasson et al. 2008). "
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    ABSTRACT: Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons. Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This biphasic dose–response relationship, displaying low-dose stimulation and a high-dose inhibition, as adaptive response to detrimental lifestyle factors determines the extent of protection from progression to metabolic diseases such as diabetes and more in general to hormonal dysregulation and age-related pathologies. Integrated responses exist to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Vitagenes encode for heat shock proteins (Hsps), thioredoxin and sirtuin protein systems. Nutritional antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways under control of Vitagene protein network. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against functional defects leading to degeneration and cell death with consequent impact on longevity processes.
    Journal of Cell Communication and Signaling 11/2014; 8(4). DOI:10.1007/s12079-014-0253-7
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    • "Several studies have shown that modulation of glutamate receptors can prevent excitation and toxicity, thereby protecting neuronal viability and function (Santangelo et al. 2012; Hovelsø et al. 2012) (Table 1). Indeed, competitive NMDAR antagonists have shown neuroprotective properties , though they cannot be adopted in the clinical practice because of the severity of side effects associated with their administration, in particular at the cognitive level (Lipton 2007). Therefore, weak antagonists of NMDARs have been investigated. "
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    ABSTRACT: Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson's disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.
    Journal of Neural Transmission 08/2014; 121(8). DOI:10.1007/s00702-013-1149-z · 2.40 Impact Factor
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