Pentoxifylline Reverses Oxidative Mitochondrial Defect in Claudicating Skeletal Muscle

The Journal of Surgical Research. Feb, 2002  |  Pubmed ID: 11796008

Previous morphologic studies and phosphorus nuclear magnetic resonance spectroscopy (31P MRS) have suggested a primary mitochondrial defect in claudicating skeletal muscle. We hypothesized that pentoxifylline may alleviate this defect.

Regarding "Can Carotid Endarterectomy Improve Metabolic Status in Patients with Asymptomatic Internal Carotid Artery Flow Lesion? Studies with Localized in Vivo Proton Magnetic Resonance Spectroscopy"

Journal of Vascular Surgery : Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter. Sep, 2002  |  Pubmed ID: 12218997

Tracking Superparamagnetic Iron Oxide Labeled Monocytes in Brain by High-field Magnetic Resonance Imaging

Journal of Neuroscience Research. Aug, 2003  |  Pubmed ID: 12868062

Inflammatory cells, most notably mononuclear phagocytes (MP; macrophages and microglia), play a critical role in brain homeostasis, repair and disease. One important event in cellular biodynamics is how MP move in and throughout the nervous system. Prior studies have focused principally on cell migration across the blood-brain barrier during neuroinflammatory processes with little work done on cell movement within the brain. During the past decade our laboratories have studied the role of MP in HIV-1-associated dementia (HAD). In HAD MP incite sustained glial inflammatory reactions causing significant neuronal damage. To extend these works we investigated cell movement in brain and its influence for disease in a novel co-registration system integrating neuropathology with high-field magnetic resonance imaging (MRI). Human monocytes labeled with superparamagnetic iron oxide particles were injected into the brain of severe combined immunodeficient (SCID) mice. MRI was recorded 1, 7, and 14 days after cell injection. MRI co-registered with histology verified that the MRI signal modification was due to the labeled cells. MRI showed human monocyte-derived macrophages along the injection site, the corpus callosum, the ventricular system and in other brain sites. These data support the idea that cell migration can be monitored in vivo and provides an opportunity to assess monocyte mobility in brain and its affects on neurodegenerative processes and notably HAD.

Advances in Neuroimaging for HIV-1 Associated Neurological Dysfunction: Clues to the Diagnosis, Pathogenesis and Therapeutic Monitoring

Current HIV Research. Jan, 2004  |  Pubmed ID: 15053341

Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable.

Quantitative 1H Magnetic Resonance Spectroscopic Imaging Determines Therapeutic Immunization Efficacy in an Animal Model of Parkinson's Disease

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Feb, 2005  |  Pubmed ID: 15716405

Nigrostriatal degeneration, the pathological hallmark of Parkinson's disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease. We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease. When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished. MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals. Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections. These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD.

Development of a Macrophage-based Nanoparticle Platform for Antiretroviral Drug Delivery

Blood. Oct, 2006  |  Pubmed ID: 16809617

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 microM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4(+) T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.

Quantitative Magnetic Resonance and SPECT Imaging for Macrophage Tissue Migration and Nanoformulated Drug Delivery

Journal of Leukocyte Biology. Nov, 2006  |  Pubmed ID: 16908517

We posit that the same mononuclear phagocytes (MP) [bone marrow (BM) and blood monocytes, tissue macrophages, microglia, and dendritic cells] which serve as targets, reservoirs, and vehicles for HIV dissemination, can be used as vehicles for antiretroviral therapy (ART). Toward this end, BM macrophages (BMM) were used as carriers for nanoparticle-formulated indinavir (NP-IDV), and the cell distribution was monitored by single photon emission computed tomography (SPECT), transverse relation time (T2)* weighted magnetic resonance imaging (MRI), histology, and gamma-scintillation spectrometry. BMM labeled with super paramagnetic iron oxide and/or 111indium oxine were infused i.v. into naïve mice. During the first 7 h, greater than 86% of cell label was recorded within the lungs. On Days 1, 3, 5, and 7, less than 10% of BMM were in lungs, and 74-81% and 13-18% were in liver and spleen, respectively. On a tissue volume basis, as determined by SPECT and MRI, BMM densities in spleen and liver were significantly greater than other tissues. Migration into the lymph nodes on Days 1 and 7 accounted for 1.5-2% of the total BMM. Adoptive transfer of BMM loaded with NP-IDV produced drug levels in lymphoid and nonlymphoid tissues that exceeded reported therapeutic concentrations by 200- to 350-fold on Day 1 and remained in excess of 100- to 300-fold on Day 14. These data show real-time kinetics and destinations of macrophage trafficking and demonstrate the feasibility of monitoring macrophage-based, nanoformulated ART.

Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson's Disease

Clinical Neuroscience Research. Dec, 2006  |  Pubmed ID: 18060039

Neuroinflammatory processes play a significant role in the pathogenesis of Parkinson's disease (PD). Epidemiologic, animal, human, and therapeutic studies all support the presence of an neuroinflammatory cascade in disease. This is highlighted by the neurotoxic potential of microglia . In steady state, microglia serve to protect the nervous system by acting as debris scavengers, killers of microbial pathogens, and regulators of innate and adaptive immune responses. In neurodegenerative diseases, activated microglia affect neuronal injury and death through production of glutamate, pro-inflammatory factors, reactive oxygen species, quinolinic acid amongst others and by mobilization of adaptive immune responses and cell chemotaxis leading to transendothelial migration of immunocytes across the blood-brain barrier and perpetuation of neural damage. As disease progresses, inflammatory secretions engage neighboring glial cells, including astrocytes and endothelial cells, resulting in a vicious cycle of autocrine and paracrine amplification of inflammation perpetuating tissue injury. Such pathogenic processes contribute to neurodegeneration in PD. Research from others and our own laboratories seek to harness such inflammatory processes with the singular goal of developing therapeutic interventions that positively affect the tempo and progression of human disease.

Quantitative Diffusion Tensor Imaging Detects Dopaminergic Neuronal Degeneration in a Murine Model of Parkinson's Disease

Neurobiology of Disease. Jun, 2007  |  Pubmed ID: 17428671

Early diagnosis of Parkinson's disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect >50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p<0.005) and decreased fractional anisotropy (p<0.03) in the substantia nigra (SN) of 5- to 7-day MPTP-treated animals when compared to saline controls. Transverse diffusivity demonstrated the most significant differences (p < or = 0.002) and correlated with the numbers of SN dopaminergic neurons (r=-0.75, p=0.012). No differences were found in the striatum, corpus callosum, cerebral cortex, or ventricles. These results demonstrate that DTI may be used as a surrogate biomarker of nigral dopaminergic neuronal degeneration.

Diffusion Tensor Metrics, T2 Relaxation, and Volumetry of the Naturally Aging Human Caudate Nuclei in Healthy Young and Middle-aged Adults: Possible Implications for the Neurobiology of Human Brain Aging and Disease

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Jan, 2008  |  Pubmed ID: 18050345

In this study of a cohort of 33 young and middle-age adults (19-59 years) we report simultaneous measurements of normal age-related changes in the caudate nuclei volume, diffusion tensor metrics, and T(2) relaxation time. Both the absolute caudate volume and its ratio relative to the total intracranial volume decreased rapidly with age in both men and women (r = -0.55; P < 0.001). The fractional diffusion tensor anisotropy of the caudate nuclei increased with age in both males and females (r = 0.48; P = 0.005). The corresponding age correlations of the caudate axial (r = 0.17; P = 0.35), transverse (r = -0.12; P = 0.50), mean diffusivities (r = 0.018; P = 0.92), and T(2) relaxation times (r = 0.194; P = 0.28) were weaker and did not reach statistical significance (P > 0.05). Our preliminary findings warrant further studies on the older and aging adults and indicate that caudate diffusion tensor imaging-derived metrics can be used as surrogates in modeling the neuronal substrates of gray matter atrophy.

Ingress of Blood-borne Macrophages Across the Blood-brain Barrier in Murine HIV-1 Encephalitis

Journal of Neuroimmunology. Aug, 2008  |  Pubmed ID: 18653244

Blood-borne macrophage ingress into brain in HIV-1 associated neurocognitive disorders governs the tempo of disease. We used superparamagnetic iron-oxide particles loaded into murine bone marrow-derived macrophages (BMM) injected intravenously into HIV-1 encephalitis mice to quantitatively assess BMM entry into diseased brain regions. Magnetic resonance imaging tests were validated by histological coregistration and enhanced image processing. The demonstration of robust BMM migration into areas of focal encephalitis provide 'proof of concept' for the use of MRI to monitor macrophage ingress into brain.

Effects of Transcranial Ultrasound and Intravenous Microbubbles on Blood Brain Barrier Permeability in a Large Animal Model

Ultrasound in Medicine & Biology. Dec, 2008  |  Pubmed ID: 18692294

We sought to determine whether transtemporal-applied 1-MHz ultrasound-induced microbubble destruction may be a safe method of transiently altering blood brain barrier (BBB) permeability for drug delivery in a large animal model. Endothelial cells are an integral component of the BBB but also prevent passage of potentially therapeutic drugs. Ultrasound-mediated destruction (UMD) of microbubbles has been shown to disrupt this barrier in small animals when ultrasound is delivered through bone windows. However, the effects of temporal bone attenuation and scattering in a large animal may limit the clinical application of such a technique. Twenty-four pigs were studied. One-MHz pulsed-wave ultrasound at 2.0 W/cm(2) (20% duty cycle) across the temporal bone was applied for 30 min after intravenous injections of either albumin-coated perfluorocarbon microbubble (PESDA, 8 pigs), lipid-encapsulated perfluorocarbon microbubbles (LEMB, 8 pigs) or ultrasound alone (8 pigs). BBB leak was quantified at 30 and 120 min after insonation using Evans blue. Serial magnetic resonance imaging (MRI) was performed in nine of the pigs (3 for each group) to quantify Gadolinium leak within the parenchyma. Peak negative pressures decreased ten-fold when ultrasound was transmitted across the pig temporal bone. Despite this, spectrophotometric analysis showed that both IV LEMB and PESDA combined with transtemporal ultrasound resulted in a significant increase in Evans blue extravasation across BBB of the treated side at 30 min after insonation (p < 0.001; compared with ultrasound alone) but not at 120 min. There was significant retention of Gadolinium within the insonified parenchyma at 60 and 90 min after insonation, but not at 120 min. Oxygen saturation and arterial pressures were not changed after any microbubble injection. Intravenous microbubbles, combined with transtemporal ultrasound, can transiently increase BBB permeability in a large animal. This induced opening of BBB is reversible and may be a safe noninvasive method of achieving drug or gene delivery across the BBB.

Facilitated Monocyte-macrophage Uptake and Tissue Distribution of Superparmagnetic Iron-oxide Nanoparticles

PloS One. 2009  |  Pubmed ID: 19183814

We posit that the same mononuclear phagocytes (MP) that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP) and tissue delivery.

A Semi-automatic Image Segmentation Method for Extraction of Brain Volume from in Vivo Mouse Head Magnetic Resonance Imaging Using Constraint Level Sets

Journal of Neuroscience Methods. May, 2009  |  Pubmed ID: 19428546

In vivo magnetic resonance imaging (MRI) of mouse brain has been widely used to non-invasively monitor disease progression and/or therapeutic effects in murine models of human neurodegenerative disease. Segmentation of MRI to differentiate brain from non-brain tissue (usually referred to as brain extraction) is required for many MRI data processing and analysis methods, including coregistration, statistical parametric analysis, and mapping to brain atlas and histology. This paper presents a semi-automatic brain extraction technique based on a level set method with the incorporation of user-defined constraints. The constraints are derived from the prior knowledge of brain anatomy by defining brain boundary on orthogonal planes of the MRI. Constraints are incorporated in the level set method by spatially varying the weighting factors of the internal and external forces and modifying the image gradient (edge) map. Both two-dimensional multislice and three-dimensional versions of the brain extraction technique were developed and applied to MRI data with minimal brain/non-brain contrast T(1)-weighted (T(1)-wt) FLASH and maximized contrast T(2)-weighted (T(2)-wt) RARE. Results were evaluated by calculating the overlap measure (OM) between the automatically segmented and manually traced brain volumes. Results demonstrate that this technique accurately extracts the brain volume (mean OM=94%) and consistently outperformed the region growing method applied to the T(2)-wt RARE MRI (mean OM=81%). This method not only successfully extracts the mouse brain in low and high contrast MRI, but can also be used to segment other organs and tissues.

Effects of Pluronic and Doxorubicin on Drug Uptake, Cellular Metabolism, Apoptosis and Tumor Inhibition in Animal Models of MDR Cancers

Journal of Controlled Release : Official Journal of the Controlled Release Society. May, 2010  |  Pubmed ID: 20074598

Cancer chemotherapy is believed to be impeded by multidrug resistance (MDR). Pluronic (triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), PEO-b-PPO-b-PEO) were previously shown to sensitize MDR tumors to antineoplastic agents. This study uses animal models of Lewis lung carcinoma (3LL-M27) and T-lymphocytic leukemia (P388/ADR and P388) derived solid tumors to delineate mechanisms of sensitization of MDR tumors by Pluronic P85 (P85) in vivo. First, non-invasive single photon emission computed tomography (SPECT) and tumor tissue radioactivity sampling demonstrate that intravenous co-administration of P85 with a Pgp substrate, 99Tc-sestamibi, greatly increases the tumor uptake of this substrate in the MDR tumors. Second, 31P magnetic resonance spectroscopy (31P-MRS) in live animals and tumor tissue sampling for ATP suggest that P85 and doxorubicin (Dox) formulations induce pronounced ATP depletion in MDR tumors. Third, these formulations are shown to increase tumor apoptosis in vivo by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and reverse transcription polymerase chain reaction (RT-PCR) for caspases 8 and 9. Altogether, formulation of Dox with P85 results in increased inhibition of the growth solid tumors in mice and represents novel and promising strategy for therapy of drug resistant cancers.

Macrophage Delivery of Therapeutic Nanozymes in a Murine Model of Parkinson's Disease

Nanomedicine (London, England). Apr, 2010  |  Pubmed ID: 20394532

Parkinson's disease is a common progressive neurodegenerative disorder associated with profound nigrostriatal degeneration. Regrettably, no therapies are currently available that can attenuate disease progression. To this end, we developed a cell-based nanoformulation delivery system using the antioxidant enzyme catalase to attenuate neuroinflammatory processes linked to neuronal death.

Development of a Macromolecular Prodrug for the Treatment of Inflammatory Arthritis: Mechanisms Involved in Arthrotropism and Sustained Therapeutic Efficacy

Arthritis Research & Therapy. 2010  |  Pubmed ID: 20836843

The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis.

Loss of Neuronal Integrity During Progressive HIV-1 Infection of Humanized Mice

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2011  |  Pubmed ID: 21368026

Neuronal damage induced by ongoing human immunodeficiency virus type 1 (HIV-1) infection was investigated in humanized NOD/scid-IL-2Rγ(c)(null) mice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4(+) T-cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in cortical N-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin, and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity after HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.

Landmark Optimization Using Local Curvature for Point-based Nonlinear Rodent Brain Image Registration

International Journal of Biomedical Imaging. 2012  |  Pubmed ID: 21966289

Purpose. To develop a technique to automate landmark selection for point-based interpolating transformations for nonlinear medical image registration. Materials and Methods. Interpolating transformations were calculated from homologous point landmarks on the source (image to be transformed) and target (reference image). Point landmarks are placed at regular intervals on contours of anatomical features, and their positions are optimized along the contour surface by a function composed of curvature similarity and displacements of the homologous landmarks. The method was evaluated in two cases (n = 5 each). In one, MRI was registered to histological sections; in the second, geometric distortions in EPI MRI were corrected. Normalized mutual information and target registration error were calculated to compare the registration accuracy of the automatically and manually generated landmarks. Results. Statistical analyses demonstrated significant improvement (P < 0.05) in registration accuracy by landmark optimization in most data sets and trends towards improvement (P < 0.1) in others as compared to manual landmark selection.

A Method for the Making and Utility of Gadolinium-labeled Albumin Microbubbles

Magnetic Resonance Imaging. Jan, 2012  |  Pubmed ID: 22056512

Perfluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA) binds scavenger receptors and can be noninvasively imaged. To enhance imaging, gadolinium (Gd)-labeled PESDA was developed and tested in a model of vascular inflammation by magnetic resonance imaging (MRI).