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This study investigates the participation of PI3Kγ in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ−/−) or with loss of kinase activity. Neutrophils recovered from the inflamed joint were quantified and stained for phosphorylated Akt (pAkt) and production of reactive oxygen species (ROS). The adherence of leukocytes to the joint microvasculature was assessed by intravital microscopy and cleaved caspase‐1 by Western blot. Injection of MSU crystals induced massive accumulation of neutrophils expressing phosphorylated Akt. In the absence of PI3Kγ, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kγ reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kγ−/−mice produced less ROS than wild‐type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kγ. In addition, in the absence of PI3Kγ activity, there was reduction of cleaved caspase‐1 and IL‐1β production in synovial tissue after injection of MSU crystals and leukotriene B4. Our studies suggest that PI3Kγ is crucial for MSU crystal–induced acute joint inflammation. It is necessary for regulating caspase‐1 activation and for mediating neutrophil migration and activation. Drugs that impair PI3Kγ function may be useful to control acute gout inflammation. PI3Kγ is an important contributor to caspase‐1 activation in earlier events after MSU crystals and LTB4 stimulation.

Zika virus is a mosquito-borne virus that is associated with neurodegenerative diseases, including Guillain–Barré syndrome1and congenital Zika syndrome2. As Zika virus targets the nervous system, there is an urgent need to develop therapeutic strategies that inhibit Zika virus infection in the brain. Here, we have engineered a brain-penetrating peptide that works against Zika virus and other mosquito-borne viruses. We evaluated the therapeutic efficacy of the peptide in a lethal Zika virus mouse model exhibiting systemic and brain infection. Therapeutic treatment protected against mortality and markedly reduced clinical symptoms, viral loads and neuroinflammation, as well as mitigated microgliosis, neurodegeneration and brain damage. In addition to controlling systemic infection, the peptide crossed the blood–brain barrier to reduce viral loads in the brain and protected against Zika-virus-induced blood–brain barrier injury. Our findings demonstrate how engineering strategies can be applied to develop peptide therapeutics and support the potential of a brain-penetrating peptide to treat neurotropic viral infections.

Infection by one of the four serotypes of the arthropod‐borne dengue virus produces a spectrum of disease manifestations, ranging from asymptomatic to life‐threatening Dengue hemorrhagic fever/Dengue shock syndrome (DHF/DSS). During the last several decades, dengue has spread its geographic distribution to become the most common arboviral infection of humans in the subtropical and tropical regions of the world. There is no specific treatment or vaccine approved for human use. This fact, associated with the large number of infected individuals and the lack of markers that indicate which patients will develop severe disease, place an enormous burden on health systems of affected countries. Many efforts have been made to elucidate several aspects of dengue disease, but the pathogenesis of disease is complex and remains unclear. The hallmark of severe dengue disease is a short‐lived plasma leakage that is believed to be immune mediated. Understanding the mechanism(s) that underlie the pathogenesis of dengue is critical for the development of safe therapeutics to prevent DHF/DSS. In this review, we highlight potential therapeutic alternatives to treat dengue infection and outline strategies used to develop and research anti‐dengue therapies, focusing on in vivo results obtained using the experimental animal models currently available. Within this context, we discuss the therapeutic potential of novel antiviral molecules, either targeting virus‐encoded functions or the cellular functions needed for viral replication. In addition, we discuss studies using anti‐inflammatory strategies aimed at reducing the exacerbated host response against infection and their potential as promising therapeutic alternatives in severe dengue disease. Drug Dev Res 72:480–500, 2011. © 2011 Wiley‐Liss, Inc.

Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridaefamily. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas.

ABSTRACTZika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivoexperiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.IMPORTANCEZika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitroand in vivo. These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment.