Cholinergic neurons respond to the administration of nerve growth factor (NGF) in vivo with a prominent and selective increase of choline acetyl transferase activity. This suggests the possible involvement of endogenous NGF, acting through its receptor TrkA, in the maintenance of central nervous system cholinergic synapses in the adult rat brain. To test this hypothesis, a small peptide, C(92-96), that blocks NGF-TrkA interactions was delivered stereotactically into the rat cortex over a 2-week period, and its effect and potency were compared with those of an anti-NGF monoclonal antibody (mAb NGF30). Two presynaptic antigenic sites were studied by immunoreactivity, and the number of presynaptic sites was counted by using an image analysis system. Synaptophysin was used as a marker for overall cortical synapses, and the vesicular acetylcholine transporter was used as a marker for cortical cholinergic presynaptic sites. No significant variations in the number of synaptophysin-immunoreactive sites were observed. However, both mAb NGF30 and the TrkA antagonist C(92-96) provoked a significant decrease in the number and size of vesicular acetylcholine transporter-IR sites, with the losses being more marked in the C(92-96) treated rats. These observations support the notion that endogenously produced NGF acting through TrkA receptors is involved in the maintenance of the cholinergic phenotype in the normal, adult rat brain and supports the idea that NGF normally plays a role in the continual remodeling of neural circuits during adulthood. The development of neurotrophin mimetics with antagonistic and eventually agonist action may contribute to therapeutic strategies for central nervous system degeneration and trauma.Nerve growth factor (NGF) is the first well characterized member of a family of neurotrophic factors (NTFs) (1) that includes brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 4 (2, 3). These neurotrophins are known to regulate the survival, differentiation, and phenotypic maintenance of specific neuronal populations, but their role in neuronal plasticity is not fully understood. Investigations in newborn and adult rats have shown that cholinergic neurons in the corpus striatum and those in the basal forebrain projecting to the hippocampus and cortex respond to exogenous NGF with a selective and prominent increase of choline acetyl transferase (ChAT) activity (4-8). These areas are the major targets of ascending projections from cholinergic basal forebrain neurons that retrogradely transport NGF from these areas to the cholinergic cell bodies of the basal forebrain (9, 10). The intracerebral application of NGF prevents the downregulation of cholinergic markers in septal cholinergic neurons after axotomy (11) and ameliorates both cholinergic and behavioral deficits after basalocortical lesions (12, 13).Another cholinergic phenotype-specific protein is the vesicular acetylcholine transporter (VAChT) (14). This molecule mobilizes cytosolic acetylcholine (ACh) into the synaptic vesicle...
The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe side effects and limited efficacy; and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted. Growth factor receptors are one of the most extensively studied tumor markers. The implication of growth factor receptors in the pathogenesis and evolution of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to tumor markers with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. This review will focus on current developments of selective targeting and bypassing drug resistance in the management of growth factor receptor-overexpressing tumors.
A novel surface receptor complex involved in inhibition of T-cell proliferation is described. Biochemical isolation revealed two non-covalently associated proteins of about M(r) 65,000 (p65) and 95,000 (p95). These polypeptides may be related. The p65 form is expressed after cellular activation and replication and is recognized by monoclonal antibody (mAb) 87.92.6 or reovirus hemagglutinin as unnatural ligands. The p95 species is associated with tyrosine kinase enzymatic activity. Receptor ligation results in rapid alteration of the phosphotyrosine content of cellular substrates, and this activity correlates with antiproliferative effects. The inhibition of proliferation is a time-dependent reversible arrest at the G1-S phase of the cell cycle. Activation through the T-cell receptor, protein kinase C, or addition of cytokines does not reverse the antiproliferative effect. This receptor complex may define novel features of T-cell proliferation.
Neurotrophins (NTFs) are a family of polypeptide growth factors that control the apoptotic death or survival, growth, and differentiation of neurons. NTFs also regulate several other cell populations such as lymphoid, epithelial, oligoglia, and mast cells. Disregulation of the NTFs or their receptors plays a key role (etiological or upstream) in certain human pathologies. Hyperactivity may lead to inflammatory pain, or some forms of cancer by autocrine/paracrine growth. Loss of activity may lead to neurodegeneration, neuropathic pain, or some forms of cancer by absence of differentiation. Consequently the NTFs and their receptors are important therapeutic targets, and pharmacological modulation may have applications ranging from treatment of chronic or acute neurodegeneration, some forms of cancer, and chronic pain (with agonists); and some forms of cancer or acute pain (with antagonists).
Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydroosmotic equilibrium and, to a lesser extent, on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, arginine vasopressin (AVP), and hence are competitive ligands. Peptides that reproduce specific sequences of a given receptor have lately been reported to interfere with its action, and if such molecules arise from regions remote from the binding site they would be anticipated to exhibit noncompetitive antagonism, but this has yet to be shown for V2R. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, cravky (labeled VRQ397), was characterized. VRQ397 was potent (IC(50) = 0.69 +/- 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function, specifically desmopressin-L-desamino-8-arginine-vasopressin (DDAVP)-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events. A dose-response profile revealed a noncompetitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). Specificity of VRQ397 was further confirmed by its inability to bind to homologous V1 and oxytocin receptors and its inefficacy to alter responses to stimulation of these receptors. VRQ397 exhibited pharmacological permissiveness on V2R-induced signals, as it inhibited DDAVP-induced PGI(2) generation but not that of cAMP or recruitment of beta-arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. We hereby describe the discovery of a first potent noncompetitive antagonist of V2R, which exhibits functional selectivity, in line with properties of a negative allosteric modulator.
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