The identification of novel drug targets for the treatment of ischemic stroke is currently an urgent challenge. Recent experimental findings have highlighted the neuroprotective potential of immunomodulatory strategies, based on polarization of myeloid cells towards non-inflammatory, beneficial phenotypes. Given the role of retinoid X receptors (RXR) in myeloid cells differentiation and polarization, here we have explored the neuroprotective potential of the RXR agonist bexarotene in mice subjected to focal cerebral ischemia.

 Acute administration of bexarotene significantly reduced blood brain barrier leakage, brain infarct damage and neurological deficit produced by transient middle cerebral artery occlusion in mice, without affecting cerebral blood flow. The rexinoid exerted neuroprotection with a wide time-window, being effective when administered up to 4.5 hours after the insult. The amelioration of histological outcome, as well as the ability of bexarotene to revert middle cerebral artery occlusion (MCAo)-induced spleen atrophy, was antagonised by BR1211, a pan-RXR antagonist, or by the selective peroxisome proliferator-activated receptor (PPAR)γ antagonist bisphenol A diglycidyl ether (BADGE), highlighting the involvement of the RXR/PPARγ heterodimer in the beneficial effects exerted by the drug. Immunofluorescence analysis revealed that bexarotene elevates Ym1-immunopositive N2 neutrophils both in the ipsilateral hemisphere and in the spleen of mice subjected to transient middle cerebral artery occlusion, pointing to a major role for peripheral neutrophil polarization in neuroprotection.

Thus, our findings suggest that the RXR agonist bexarotene exerts peripheral immunomodulatory effects under ischemic conditions to be effectively repurposed for the acute therapy of ischemic stroke.

To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.

Retinal ganglion cell (RGC) death is the final event leading to visual impairment in glaucoma; therefore, identification of neuroprotective strategies able to slow down or prevent the process is one of the main challenges for glaucoma research. The purpose of this study was to evaluate the neuroprotective potential of RGC death induced by the in vivo transient increase in intraocular pressure (IOP) of a combined treatment with forskolin, homotaurine, and L-carnosine. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is an activator of adenylate cyclase that decreases IOP by reducing aqueous humor production and functions as a neuroprotector due to its neurotrophin-stimulating activity. Homotaurine is a natural aminosulfonate compound endowed with neuromodulatory effects, while the dipeptide L-carnosine is known for its antioxidant properties.

Dear Sir,

On 13th-14th June, the University of Calabria (Rende, Cosenza, Italy) provided the venue for "DRUG REPURPOSING AND BEYOND: THE FUNDAMENTAL ROLE OF PHARMACOLOGY", the first Italian meeting devoted to this hot topic. It is widely recognized that the time lag between filing a basic patent on a new molecular entity and the the commercialization of that entity as a drug is extremely long and costly, taking more than 11-12 years, and generating an average cost estimated to be in excess of US$1 billion (Sternitzke, 2010). It is calculated [...]

The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.

Sul numero di Nature del 7 gennaio scorso è stato pubblicato uno studio preclinico che indica la teixobactina come una possibile risposta al problema della resistenza batterica agli antibiotici. Prodotta dal metabolismo secondario di una specie batterica che normalmente non cresce in laboratorio, la teixobactina si lega a frazioni lipidiche della parete batterica e ne inibisce la sintesi. Tale meccanismo non sembra generare specie mutanti di stafilocco aureo meticillino resistente o di micobatterio della tubercolosi resistenti al trattamento con l’antibiotico. Ulteriori studi dovranno confermare questa che sembra più di una speranza nella lotta alla resistenza di specie batteriche responsabili di gravi e difficilmente curabili infezioni nell’uomo.

 Prof Giacinto Bagetta

Link: A new antibiotic kills pathogens without detectable resistance.

Il recettore per i prodotti finali della glicazione avanzata (RAGE) interagisce con diverse molecole implicate nell’omeostasi, nello sviluppo e nell’infiammazione. Studi recenti hanno documentato come questo recettore multi-ligando sia coinvolto nella patogenesi di malattie vascolari incluso lo stroke. A seguito di ischema focale, l’espressione cerebrale dell’isoforma di membrana full-lenght di RAGE viene modulata in maniera dipendente dall’intensità dell’insulto, mentre i livelli plasmatici dell’isoforma solubile (sRAGE) risultano ridotti (Greco et al. 2012 – link: http://www.ncbi.nlm.nih.gov/pubmed/22528836). Attraverso il legame con i prodotti finali della glicazione avanzata, sRAGE ne impedisce il legame alla forma full-lenght, riducendo di conseguenza gli effetti neurotossici derivanti dall’attivazione del recettore di membrana. Al fine di chiarire il ruolo di RAGE nella patofisiologia ischemica, lo studio di recente pubblicato sull’European Journal of Pharmacology descrive la modulazione dell’espressione di RAGE full-lenght a livello del core e della penombra cerebrali e di sRAGE nel plasma di ratti sottoposti ad ischemia focale transitoria trattati con il farmaco neuroprotettivo PJ34 (inibitore dell’enzima poli-ADP-ribosio polimerasi). I dati ottenuti supportano il potenziale di RAGE come marcatore della gravità della patologia ischemica e dell’efficacia di farmaci neuroprotettivi.