Cannabinoid rescue of striatal progenitor cells in chronic Borna Disease viral encephalitis in rats

Department of Neurology, University of California-Irivne, Irvine, California 92697-4292, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 06/2008; 14(3):252-60. DOI: 10.1080/13550280802074521
Source: PubMed


A growing number of environmental and pharmacologic manipulations have been shown to influence adult neurogenesis. Borna disease virus (BDV) in rats causes cortical and subcortical infection with extrapyramidal motor symptoms, and hippocampal infection suppresses neurogenesis. Given the known effects of cannabinoids in promoting neural progenitor cell survival, the authors examined in vivo effects of chronic BDV infection in rats on BrdU-positive progenitor cells in striatum, together with neuroprotective actions of cannabinoids. Birth and survival of BrdU-positive progenitor cells in striatum of BDV-infected rats treated with a general cannabinoid agonist (WIN 55,212 1 mg/kg i.p. b.i.d. x 7 days) were examined, as well as anti-inflammatory, antiviral, and nutritional effects of cannabinoids. Cannabinoid treatment protected BrdU-positive progenitor cells in striatum that were susceptible to virus-induced injury (p < .01) through suppression of microglia activation (p < .001). As a consequence of their anti-inflammatory actions and support of neural progenitor cell survival, cannabinoids may be adjunctive treatment for encephalitides with microglial inflammation and neurodegeneration.

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    • "WIN treatment significantly increased the number of BrdU + cells (BD-WIN vs BD, p<0.001, Tukey's; n=4–5 per group) (Fig 1D,E), as already shown in the SVZ alone after WIN injection (Solbrig et al., 2008). Cell counts in the habenula, a control region for bioavailability of BrdU, were similar across experimental groups (35–40 BrdU + cells per section). "
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    ABSTRACT: 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.
    Experimental Neurology 11/2010; 226(1):231-41. DOI:10.1016/j.expneurol.2010.09.003 · 4.70 Impact Factor
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    • "Furthermore, these data complement previous clinical evidence suggesting a protective role of cannabis in the neurocognitive outcomes of METH-dependent subjects (Gonzalez et al., 2004) and in the emotional effects of related neurotoxic substances, such as 3,4-methylenedioxymethamphetamine (MDMA) (Boot et al., 2000; Milani et al., 2005; Sharma and Ali, 2008). This background, together with the well-characterized neuroprotective and anti-inflammatory actions of CB 1 receptor agonists (Nagayama et al., 1999; Marsicano et al., 2003; Marchalant et al., 2007; Solbrig and Hermanowicz, 2008; for a review, see Van Der Stelt and Di Marzo, 2005) highlights the possibility that CB 1 receptor synthesis may be stimulated by METH neurotoxicity in specific regions, as a countermeasure to curtail its deleterious impact. This process is also likely supported by the involvement of dopamine and glutamate, two of the major mediators of METH neurotoxicity (Schmidt et al., 1985; Selden, 1991; Stephans and Yamamoto, 1994; Bortolato et al., 2009). "
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    ABSTRACT: Cannabis is the most common secondary illicit substance in methamphetamine (METH) users, yet the outcomes of the concurrent consumption of both substances remain elusive. Capitalizing on recent findings on the implication of CB₁ cannabinoid receptors in the behavioral effects of METH, we hypothesized that METH-induced neurotoxicity may alter the brain expression of CB₁, thereby affecting its role in behavioral functions. To test this possibility, we subjected rats to a well-characterized model of METH neurotoxicity (4 mg/kg, subcutaneous × 4 injections, 2 h apart), and analyzed their CB₁ receptor brain expression three weeks later. METH exposure resulted in significant enhancements of CB₁ receptor expression across several brain regions, including prefrontal cortex, caudate-putamen, basolateral amygdala, CA1 hippocampal region and perirhinal cortex. In parallel, a different group of METH-exposed rats was used to explore the responsiveness to the potent cannabinoid agonist WIN 55,212-2 (WIN) (0.5-1 mg/kg, intraperitoneal), within several paradigms for the assessment of emotional and cognitive functions, such as open field, object exploration and recognition, and startle reflex. WIN induced anxiolytic-like effects in METH-exposed rats and anxiogenic-like effects in saline-treated controls. Furthermore, METH-exposed animals exhibited a significantly lower impact of WIN on the attenuation of exploratory behaviors and short-term (90 min) recognition memory. Conversely, METH neurotoxicity did not significantly affect WIN-induced reductions in locomotor activity, exploration time and acoustic startle. These results suggest that METH neurotoxicity may alter the vulnerability to select behavioral effects of cannabis, by inducing distinct regional variations in the expression of CB₁ receptors.
    Journal of Psychiatric Research 04/2010; 44(14):944-55. DOI:10.1016/j.jpsychires.2010.03.002 · 3.96 Impact Factor
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    ABSTRACT: This paper presents a neural network adaptive control scheme for the nonlinear systems in strict-feedback form, where the unstructured uncertainties are assumed to be unknown, though they still satisfy certain growth conditions characterized by 'bounding functions' composed of known functions multiplied by unknown constants. All adaptation laws for these unknown bounds are derived from Lyapunov based method as well as the adaptation laws for the networks' weights estimations. In addition, the unknown control gain functions are not approximated directly by neural networks. Therefore, we can avoid the possible controller singularity problems. Under a certain relaxed assumptions on the control gain functions, proposed control scheme can guarantee that all the signals in the closed-loop system are uniformly ultimately bounded (UUB). Simulation studies are included to illustrate the effectiveness of the proposed scheme, and some practical features of the control laws are also discussed.
    Decision and Control, 2004. CDC. 43rd IEEE Conference on; 01/2005
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