Marylou V. Solbrig

A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats.

Chronic CNS infection by several families of viruses can produce deficits in prefrontal cortex (PFC) and striatal function. Cannabinoid drugs have been long known for their anti-inflammatory properties and their ability to modulate adult neuro and gliogenesis. Therefore, we explored the effects of systemic administration of the cannabinoid agonist WIN55,212-2(WIN) on prefrontal cortex (PFC) and striatal cytogenesis in a viral model of CNS injury and inflammation based on Borna Disease (BD) virus encephalitis. Active BrdU(+) progenitor populations were significantly decreased 1 week after BrdU labeling in BD rats [p<0.001 compared to uninfected (NL) controls] while less than 5% of BrdU(+) cells colabeled for BDV protein. Systemic WIN (1mg/kg i.p. twice daily×7 days) increased the survival of BrdU(+) cells in striatum (p<0.001) and PFC of BD rats, with differential regulation of labeled oligodendroglia precursors vs microglia/macrophages. WIN increased the percentage of BrdU(+) oligodendrocyte precursor cells and decreased BrdU(+) ED-1-labeled phagocytic cells, without producing pro- or antiviral effects. BDV infection decreased the levels of the endocannabinoid anandamide (AEA) in striatum (p<0.05 compared to NL rats), whereas 2-AG levels were unchanged. Our findings indicate that: 1) viral infection is accompanied by alterations of AEA transmission in the striatum, but new cell protection by WIN appears independent of its effect on endocannabinoid levels; and 2) chronic WIN treatment alters the gliogenic cascades associated with CNS injury, promoting oligodendrocyte survival. Limiting reactive gliogenesis and macrophage activity in favor of oliogodendroglia development has significance for demyelinating diseases. Moreover, the ability of cannabinoids to promote the development of biologically supportive or symbiotic oligodendroglia may generalize to other microglia-driven neurodegenerative syndromes including NeuroAIDS and diseases of aging.

Juvenile cannabinoid treatment induces frontostriatal gliogenesis in Lewis rats

Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely depends on the key influence of diverse genetic vulnerability factors. Inbred rodent strains afford a highly informative tool to study the contribution of genetic determinants to the long-term effects of juvenile cannabinoid exposure. In this study, we analyzed the phenotypical impact of the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 2mg/kg/day from postnatal day 35-48) in adolescent Lewis rats, an inbred strain exhibiting resistance to psychotomimetic effects of environmental manipulations. At the end of this treatment, WIN-injected animals displayed increased survival of new cells (mainly oligodendroglia precursors) in the striatum and prefrontal cortex (PFC), two key terminal fields of DAergic pathways. To test whether these changes may be associated with enduring behavioral alterations, we examined the consequences of adolescent WIN treatment in adulthood (postnatal days 60-70), with respect to DA levels and metabolism as well as multiple behavioral paradigms. Rats injected with WIN exhibited increased turnover, but not levels, of striatal DA. In addition, cannabinoid-treated animals displayed increases in acoustic startle latency and novel-object exploration; however, WIN treatment failed to induce overt deficits of sensorimotor gating and social interaction. These results indicate that, in Lewis rats, juvenile cannabinoid exposure leads to alterations in frontostriatal gliogenesis, as well as select behavioral alterations time-locked to high DAergic metabolism, but not overt schizophrenia-related deficits.

Current Neurological Observations and Complications of Dengue Virus Infection

Dengue, a mosquito-borne flavivirus and fastest growing tropical disease in the world, has experienced an explosion of neurologic case reports and series in recent years. Now dengue is a frequent or leading cause of encephalitis in some endemic regions, is estimated to infect one in six tourists returning from the tropics, and has been proven to have local transmission within the continental USA. High documentation of neurologic disease in recent years reflects increases in overall cases, enhanced clinical awareness and advances in diagnostics. Neurological aspects of dengue virus, along with epidemiology, treatment, and vaccine progress, are presented.

Prospects for cannabinoid therapies in viral encephalitis

Cannabinoids are promising therapies to support neurogenesis and decelerate disease progression in neuroinflammatory and degenerative disorders. Whether neuroprotective effects of cannabinoids are sustainable during persistent viral infection of the CNS is not known. Using a rodent model of chronic viral encephalitis based on Borna Disease (BD) virus, in which 1 week treatment with the general cannabinoid WIN 55,212-2 has been shown to be neuroprotective (Solbrig et al., 2010), we examine longer term (2 week treatment) effects of a general (CB1 and CB2) cannabinoid receptor agonist WIN55,212-2 (1mg/kg ip twice per day) or a specific (CB2) cannabinoid receptor agonist HU-308 (5mg/kg ip once daily) on histopathology, measures of frontostriatal neurogenesis and gliogenesis, and viral load. We find that WIN and HU-308 differ in their ability to protect new BrdU(+) cells. The selective CB2 agonist HU increases BrdU(+) cells in prefrontal cortex (PFC), significantly increases BrdU(+) cells in striatum, differentially regulates polydendrocytes vs. microglia/macrophages, and reduces immune activation at a time WIN-treated rats appear tolerant to the anti-inflammatory effect of their cannabinoid treatment. WIN and HU had little direct viral effect in PFC and striatum, yet reduced viral signal in hippocampus. Thus, HU-308 action on CB2 receptors, receptors known to be renewed during microglia proliferation and action, is a nontolerizing mechanism of controlling CNS inflammation during viral encephalitis by reducing microglia activation, as well as partially limiting viral infection, and uses a nonpsychotropic cannabinoid agonist.

Neurologic infections in diabetes mellitus

Even at a time when HIV/AIDS and immunosuppressive therapy have increased the number of individuals living with significant immunocompromise, diabetes mellitus (DM) remains a major comorbid disorder for several rare but potentially lethal infections, including rhino-orbital-cerebral mucormycosis and malignant external otitis. DM is also a commonly associated condition in patients with nontropical pyomyositis, pyogenic spinal infections, Listeria meningitis, and blastomycosis. As West Nile virus spread to and across North America over a decade ago, DM appeared in many series as a risk factor for death or neuroinvasive disease. More recently, in several large international population-based studies, DM was identified as a risk factor for herpes zoster. The relationships among infection, DM, and the nervous system are multidirectional. Viral infections have been implicated in the pathogenesis of type 1 and type 2 DM, while parasitic infections have been hypothesized to protect against autoimmune disorders, including type 1 DM. DM-related neurologic disease can predispose to systemic infection - polyneuropathy is the predominant risk factor for diabetic foot infection. Because prognosis for many neurologic infections depends on timely institution of antimicrobial and sometimes surgical therapy, neurologists caring for diabetic patients should be familiar with the clinical features of the neuroinfectious syndromes associated with DM.

Viral Hemorrhagic Fevers

Viral hemorrhagic fever (VHF) agents are dominantly from four major RNA virus families: the Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. General and hemorrhagic signs and symptoms of these viral infections are well known, but their neurological complications and clinical variants with distinct neurologic syndromes are not so famous. Pathologic features of VHF disease: systemic rapid viral replication, abnormal immune and inflammatory responses culminating in hemorrhage, edema, coagulopathies, multiorgan failure, and molecular properties, such as those shared with encephalitic members of the same family, are now, being recognized to contribute to a wide spectrum of neurologic disorders. Efforts to characterize and understand the pathogenesis of these VHF-associated central nervous system disorders are underway.

Role of infection in neurologic and psychiatric diseases.

What makes CNS injury by pathogens different from other CNS afflictions such as stroke or Alzheimers Disease is well illustrated in the manuscripts of this volume. We will see that viral, bacterial, or prion-induced injuries are dynamic and varied. No two infection cases are the same due to host or agent factors. We will encounter pathogens that are shared with other species and some that range across the globe. We will also find robust examples of gene x age x environment interactions as determinants of nervous system disease, which can be incorporated into understanding many neurobiological processes. The role of infection in neurologic and psychiatric diseases is predicated on clinical and research observations, which have been expanded into the domains of neurobiology by hypotheses from several perspectives. Our collected papers come from perspectives of epidemiology, protein biochemistry, immunology, genetics, molecular biology, pathology, behavioral sciences, psychology, neuropharmacology, and human and veterinary medicine. These articles are comprehensive reviews, topical summaries, or original research papers. We hope that this collection of manuscripts provides a greater understanding of both familiar and unfamiliar pathogens, prompts new ideas on disease mechanisms and treatments, and stimulates further cooperative work on infection in neurologic and psychiatric diseases. We thank our contributors from around the world. When it comes to transmissible diseases, the world is a small place. Although we did not specifically solicit for public health topics, we note that cross-species transfers, emerging diseases, epidemics and pandemics, are developed as key discussions in several of our manuscripts. For this reason we dedicate this special issue to the One Health Initiative, whose work is defined by the Mission Statement on their website: www.onehealthinitiative.com/mission.php “Recognizing that human and animal health and mental health.... are inextricably linked, One Health seeks to promote, improve, and defend the health and well-being of all species by enhancing cooperation and collaboration between physicians, veterinarians, and other scientific professionals....” We express our sincere gratitude to all authors and reviewers for their time and effort, to Betsy Foxman, Editor-in-Chief for the invitation, and the staff at Hindawi Publishing for their assistance and support. Marylou V. Solbrig Guey Chuen Perng

Diagnosing encephalitis? Consider human herpesvirus type 6.

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