Pathologically activated therapeutics for neuroprotection.

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: 31.38). 11/2007; 8(10):803-8. DOI: 10.1038/nrn2229
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: B cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function. Results: Non-competitive NMDAR antagonists impaired B-cell receptor (BCR)- and lipopolysaccharide (LPS)-induced B-cell proliferation, reduced B-cell migration towards the chemokines SDF-1a and CCL21 and downregulated IgM and IgG secretion. Mechanistically, these effects were mediated through a blockade of Kv1.3 and KCa3.1 potassium channels and resulted in an attenuated Ca2+-flux and activation of Erk1/2, Akt and NFATc1. Interestingly, NMDAR antagonist treatment increased the frequency of IL-10 producing B cells after BCR/CD40 stimulation. Conclusions: Non-competitive NMDAR antagonists attenuate BCR and Toll-like receptor 4 (TLR4) B-cell signaling and effector function and can foster IL-10 production. Consequently, NMDAR antagonists may be useful to target B cells in autoimmune diseases or pathological systemic inflammation. The drugs` additional side effects on B cells should be considered in treatments of neuronal disorders with NMDAR antagonists.
    Cell Communication and Signaling 12/2014; · 4.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ObjectIschemic brain injury is the leading cause for death and long-term disability in patients who suffer cardiac arrest and embolic stroke. Excitotoxicity and subsequent Ca2+-overload lead to ischemic neuron death. We explore a novel mechanism concerning the role of the excitatory extracellular calcium-sensing receptor (CaSR) in the induction of ischemic brain injury.Method Mice were exposed to forebrain ischemia and the actions of CaSR were determined after its genes were ablated specifically in hippocampal neurons or its activities were inhibited pharmacologically. Since the CaSR forms a heteromeric complex with the inhibitory type B γ-aminobutyric acid receptor 1 (GABABR1), we compared neuronal responses to ischemia in mice deficient in CaSR, GABABR1, or both, and in mice injected locally or systemically with a specific CaSR antagonist (or calcilytic) in the presence or absence of a GABABR1 agonist (baclofen).ResultsBoth global and focal brain ischemia led to CaSR overexpression and GABABR1 downregulation in injured neurons. Genetic ablation of Casr genes or blocking CaSR activities by calcilytics rendered robust neuroprotection and preserved learning and memory functions in ischemic mice, partly by restoring GABABR1 expression. Concurrent ablation of Gabbr1 gene blocked the neuroprotection caused by the Casr gene knockout. Coinjection of calcilytics with baclofen synergistically enhanced neuroprotection. This combined therapy remained robust when given 6 h after ischemia.InterpretationOur study demonstrates a novel receptor interaction, which contributes to ischemic neuron death through CaSR upregulation and GABABR1 downregulation, and feasibility of neuroprotection by concurrently targeting these two receptors.
    Annals of Clinical and Translational Neurology. 09/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Erythropoietin in the nervous system is a potential neuroprotective factor for cerebral ischemic damage due to specific-binding to the erythropoietin receptor, which is associated with survival mechanisms. However, the role of its receptor is unclear. Thus, this work assessed whether a low dose (500UI/Kg) of intranasal recombinant human erythropoietin administered 3h after ischemia induced changes in the activation of its receptor at the Tyr456-phosphorylated site in ischemic hippocampi in rats. The results showed that recombinant human erythropoietin after injury maintained cell survival and was associated with an increase in receptor phosphorylation at the Tyr456 site as an initial signaling step, which correlated with a neuroprotective effect.
    Neuroscience Letters 09/2014; · 2.06 Impact Factor


Available from