Available online at www.sciencedirect.com Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: current and emerging therapeutic options Giuseppe Pignataro 1,3 , Domenico Capone 1 , Giuliano Polichetti 1 , Antonio Vinciguerra 1 , Antonio Gentile 1 , Gianfranco Di Renzo 1,3 and Lucio Annunziato 1,2,3 The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes.It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immunosuppressant effects, are provided with neuroprotective properties. In fact, mTOR is involved in the mechanism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer’s disease, and amyotrophic lateral sclerosis. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis. Addresses 1 Division of Pharmacology, Department of Neuroscience, School of Medicine, ‘‘Federico II’’ University of Naples, Via Pansini, 5, 80131 Naples, Italy 2 SDN, Via Gianturco, 113, 80142 Naples, Italy 3 National Institute of Neuroscience, Corso Raffaello, 30, 10125 Torino, Italy Corresponding author: Annunziato, Lucio (lannunzi@unina.it) Current Opinion in Pharmacology 2011, 11:378–394 This review comes from a themed issue on Cancer Edited by Maria Fiammetta Romano Available online 7th June 2011 1471-4892/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2011.05.003 Introduction The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [1]. The molecular mechanism underlying mTOR activity consists in a phosphorylation of eIF-4E binding protein (4E-BP) and p70 ribosomal S6 protein kinase (p70S6K), two important regulators of protein translation [2–6]. The mTORC1 is involved in the control of a wide variety of cellular processes such as transcription and translation, autophagy, cell cycle and microtubule dynamics. The other mTOR complex, mTORC2, regulates actin cytos- keleton dynamics and controls the activity of two protein kinases: Akt and PKCa [5,7]. mTOR controls Akt activity by phosphorylating it at the level of serine 473 [8,9]. The canonical pathway of mTOR activation starts with its activation by mitogens, trophic factors (like brain-derived neurotrophic factor—BDNF) or hormones (insulin). This process, in turn, leads to the activation of phosphoinosi- tide-3 0 kinase (PI3K) via recruitment of the SH2 domain containing adaptor proteins and Ras, and increased pro- duction of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The immediate consequence of increased PIP3 levels is the recruitment of 3-phosphoinositide-depend- ent protein kinase 1 (PDK1) and Akt to the cell mem- brane and subsequent phosphorylation of Akt by PDK1 and mTORC2 [10] (Figure 1). Interestingly, it has been recently reported that mTOR is involved in the mech- anism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer’s disease, and amyo- trophic lateral sclerosis [11  ]. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis [12]. Regarding the regulation of mTOR pathway, the kinase activity of its downstream components is modulated both in physiological conditions by several elements such as trophic factors, mitogens, hormones, amino acids, and in pathological conditions such as cellular stress, ischemia, Current Opinion in Pharmacology 2011, 11:378–394 www.sciencedirect.com