Barry Festoff

University of Kansas Medical Center, Neurology, Faculty Member

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Professor of Neurology at the University of Kansas Medical School and Founder/CEO of pHLOGISTIX LLC in the Kansas City area to develop biotherapeutics and companion diagnostics based on co-evolution of coagulation and inflammation as host defense systems in brain and CNS. These pathways allow us to focus on developing novel therapeutic targets for brain, injury, neurodegenerative disorders, stroke and neuropsychiatric conditions presenting a paradigm shift for 21st century neurotherapeutics.
Address: Kansas City, Missouri, United States

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Papers by Barry Festoff

Biochemical Studies of Synapses in Vitro

Journal of Biological Chemistry

Page 1. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 244, No. 12, Issue of June 25, PP. 3166-3172, 19... more

Thrombin and the Coag-Inflammatory Nexus in Neurotrauma, ALS, and Other Neurodegenerative Disorders

Frontiers in Neurology

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Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration

BioMed Research International

Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s dis... more Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s disease (AD) in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs) in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i) the presence/absence of AD, (ii) the risk of developing AD, (iii) the progression of AD, or (iv) AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons) is universally present....

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HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease

Journal of neuroinflammation, Aug 24, 2016

The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease ... more The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients. We determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed...

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Sérine protéases et leurs inhibiteurs : leur rôle dans la différenciation du système neuromusculaire

Comptes Rendus Des Seances De La Societe De Biologie Et De Ses Filiales, 1994

Incorporation of [¹⁴c]-Glucosamine Into Synaptosomes in Vitro

J Neurochem, 1971

Amyotrophic Lateral Sclerosis: Current and Future Treatment Strategies

Drugs, 1996

Amyotrophic lateral sclerosis (ALS) is a fatal, enigmatic disorder characterised by relentless pr... more Amyotrophic lateral sclerosis (ALS) is a fatal, enigmatic disorder characterised by relentless progression of muscle wasting and weakness until death ensues due to respiratory muscle failure. Intellectual functions are usually spared. ALS, known also as motor neuron disease (MND) in the UK, maladie de Charcot in France and Lou Gehrig&#39;s disease in the US, is usually sporadic, but between 5 and 10% of all cases are hereditary, usually inherited as autosomal dominant. Previously thought to be untreatable, as well as incurable, just in the last 3 years ALS has been the greatest clinical application of recent exciting break-throughs in preclinical neurobiology research. Although definitive information regarding the cause(s) and pathogenesis of ALS still escapes us, meaningful demonstration of intercession in the downhill course with specific therapy has been suggested, giving reason to be hopeful, if cautiously and critically optimistic. This review focuses on the recent work from the fields of growth/trophic factors, glutamate/neurotoxicity, neuroprotection and proteases and inhibitors, as well as the approaches to measuring specific effects in patients with the illness. It ends with a eye to the horizon, and the future, and where ALS treatment strategies may be heading after the millennium.

Characterization of apoptosis in a motor neuron cell line. Point of View

Spine, Jan 15, 1998

Serum withdrawal was introduced to a spinal cord motor neuron cell line to investigate the mode o... more Serum withdrawal was introduced to a spinal cord motor neuron cell line to investigate the mode of cell death. To characterize the death of motor neurons in culture, to gain insight into mechanisms that could be important in spinal cord diseases. Normal reduction of cell number during central nervous system development is brought about by programmed cell death. These same apoptotic processes probably play a role in a variety of central nervous system disorders, including traumatic injury. Although certain proteolytic processes are involved, the molecular details involved in the apoptotic induction have not been fully elucidated. To identify apoptosis, several criteria were used, including analysis of chromatin condensation with DNA-specific stains (propidium iodide and Hoechst 33342); in situ end-labeling of DNA fragments in apoptotic nuclei with terminal deoxynucleotidyl transferase; fragmentation of DNA separated on agarose gel electrophoresis; and cleavage of a characteristic substrate for apoptotic proteases, alpha-fodrin, into signature cleavage fragments. The NSC19 cell line exhibited motor neuron characteristics morphologically, with typical cellular structure, and biochemically, by synthesizing choline acetyl transferase. Under various treatments including serum withdrawal (loss of trophic factors), cell loss occurred through an apoptotic cell death pathway. A murine motor neuron cell line, NSC19, has been used to investigate apoptosis in this in vitro system. Cell death occurs by apoptosis, suggesting that this cell line may provide a useful model for studying apoptotic mechanisms in spinal cord degeneration and injury.

Plasminogen activator inhibitor 1, the primary regulator of fibrinolysis, in normal human cerebrospinal fluid

J Neurosci Res, 1993

The occurrence of type-1 plasminogen activator inhibitor (PAI-1) in human cerebrospinal fluid (CS... more The occurrence of type-1 plasminogen activator inhibitor (PAI-1) in human cerebrospinal fluid (CSF) has not previously been reported. As a member of the serpin superfamily of serine protease inhibitors and an acute phase response component, PAI-1 has powerful potential roles in nervous system homeostasis. We have detected this serpin antigen using a polyclonal anti-PAI-1 antibody in normal human CSF. In Western blotting, PAI-1 in several CSF samples appears as a two-band antigen of Mr = 54 and 35 kDa, presumably the intact and proteolytic fragment, respectively. In vitro complex formation studies confirm that the 54 kDa form of PAI-1 interacts with 125I-urokinase after activation with SDS, but the 35 kDa form does not. Quantification of total PAI-1 antigen in 18 normal human CSF samples by ELISA reveals a mean value of 1.0 +/- 0.07 (SEM) micrograms/dL, indicating that a relatively low concentration of the inhibitor occurs in normal human CSF. This information should now allow comparison of PAI-1 levels and activity in various neurologic disorders.

Biochemical Studies of Synapses in Vitro III. IONIC ACTIVATION OF PROTEIN SYNTHESIS

Journal of Biological Chemistry, Jun 25, 1969

Adenylate cyclase system of human skeletal muscleCharacteristics of catecholamine stimulation and nucleotide regulation

Bba Gen Subjects, 1978

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Neuroprotective signal transduction in model motor neurons exposed to thrombin: G-protein modulation effects on neurite outgrowth, Ca(2+) mobilization, and apoptosis

Journal of Neurobiology, Sep 1, 2001

Thrombin, the ultimate protease in the blood coagulation cascade, mediates its known cellular eff... more Thrombin, the ultimate protease in the blood coagulation cascade, mediates its known cellular effects by unique proteolytic activation of G-protein-coupled protease-activated receptors (PARs), such as PAR1, PAR3, and PAR4, and a &quot;tethered ligand&quot; mechanism. PAR1 is variably expressed in subpopulations of neurons and largely determines thrombin&#39;s effects on morphology, calcium mobilization, and caspase-mediated apoptosis. In spinal cord motoneurons, PAR1 expression correlates with transient thrombin-mediated [Ca(2+)](i) flux, receptor cleavage, and elevation of rest [Ca(2+)](i) activating intracellular proteases. At nanomolar concentrations, thrombin retracts neurites via PAR1 activation of the monomeric, 21 kDa Ras G-protein RhoA, which is also involved in neuroprotection at lower thrombin concentrations. Such results suggest potential downstream targets for thrombin&#39;s injurious effects. Consequently, we employed several G-protein-specific modulators prior to thrombin exposure in an attempt to uncouple both heterotrimeric and monomeric G-proteins from motoneuronal PAR1. Cholera toxin, stimulating Gs, and lovastatin, which blocks isoprenylation of Rho, reduced thrombin-induced calcium mobilization. In contrast, pertussis toxin and mastoparan, inhibiting or stimulating G(o)/G(i), were found to exacerbate thrombin action. Effects on neuronal rounding and apoptosis were also detected, suggesting therapeutic utility may result from interference with downstream components of thrombin signaling pathways in human motor neuron disorders, and possibly other neurodegenerative diseases. Published 2001 John Wiley &amp; Sons, Inc.

Thrombospodin, a platelet α-granule and matrix glycoprotein, is increased in muscle basement membrane of patients wiht amyotrophic lateral sclerosis

Journal of the Neurological Sciences, 1992

Upregulation of Neurotoxic Serine Proteases, Prothrombin, and Protease-Activated Receptor 1 Early After Spinal Cord Injury

Journal of Neurotrauma, 2000

Apoptosis, well-established in development and now also in degenerative disease, occurs with regu... more Apoptosis, well-established in development and now also in degenerative disease, occurs with regularity in several cell compartments early after controlled contusion spinal cord injury (SCI). Cell death in astrocytic, microglial, and neuronal populations peaks at 3 days, while oligodendroglial apoptosis is found 10-14 days later. In this regard, the executioners of apoptosis, the caspase proteases, are also activated within 3 days of SCI. On the other hand, serine proteases, which have been shown to initiate apoptosis and activate caspases in culture models, have not been extensively studied in regards to nervous system trauma. As part of an ongoing effort to examine the spectrum of genes that are up- and downregulated in the injured rat spinal cord, we synthesized serine protease family specific primers to take advantage of conserved residues in the charge relay system and the codon preferences of these mammalian genes. These primers were then employed in a modified, family-specific differential mRNA display technique. One specific serine protease gene we found that was upregulated after injury was prothrombin. Qualitative and quantitative RT-PCR techniques indicated that this increase occurred early, already evident at 8 h after injury, and reached a maximum level fourfold above baseline at 24 h. Peak expression for prothrombin mRNA occurred prior to peak levels of apoptosis in astrocytic, microglial and neuronal compartments at 72 h. Of additional interest, gene database mining revealed that prothrombin shared approximately 48% similarity with myelencephalon-specific protease (MSP), a neurotoxic serine protease previously found to be increased two- to threefold at 3 days after excitotoxic SCI. Since thrombin induces apoptosis in murine and chick motor and rat hippocampal neurons by activating a member of the novel protease-activated receptor (PAR) gene family known as PAR-1, we also analyzed PAR-1 by similar techniques and found that it, too, was upregulated after SCI with the same kinetics as prothrombin. We confirmed these results with gene array analyses that revealed more than one trypsin subfamily serine protease was activated by SCI. They imply the possibility of using specific, tissue-directed serine protease inhibition at translational or transcriptional levels, and offer a potential paradigm shift in drug discovery for SCI to limit the extent of apoptosis, and consequent functional loss, in the human spinal cord.

/n Vitro Studies of Skeletal Muscle Membranes* Adenylate Cyclase of Fast and Slow Twitch Muscle and the Effects of Denervation

J Membrane Biol, 1977

Prospects for the Pharmacotherapy of Amyotrophic Lateral Sclerosis: Old Strategies and New Paradigms for the Third Millennium

Cns Drugs, Feb 1, 2003

Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly develo... more Biomedical researchers interested in amyotrophic lateral sclerosis (ALS) must invoke newly developing technologies if we are to discover pharmaceutical treatments that will help a significant population of patients with the disease. The focus of ALS research over the last 10 years has been on reactive oxygen species (ROS) and glutamate excitotoxicity, resulting in several clinical trials and the launch of the only drug currently available for the treatment of ALS, riluzole. Unfortunately, the therapeutic benefits have been minimal, at best, and the prognosis for patients with ALS has not improved beyond very modest retardation of the disease course. By emphasising ROS and glutamate excitotoxicity, current ALS research has only partially been able to attenuate the rate of motor decline and neuronal loss associated with this illness. Clues to additional therapeutic potentialities will come from an increased understanding of the mode of cell death (apoptotic or other) and the pathways leading to neuronal demise. If death is apoptotic, inhibiting caspases may be useful. The regulatory modifications for cell death at the molecular level remain to be determined and exploited to prevent neuronal loss, although novel pathways have been recently elucidated that impact on protein aggregation and processing. Oxidative stress, seen in both familial and sporadic forms of ALS, may be only one post-translational mechanism likely to affect specific proteins essential for the health and stability of motor neurons. Protein cross-linking by transglutaminase paralleling that may lead to defects in proteasome function may also be a significant mechanism. The latest capabilities to screen protein changes in specific cells represent the kinds of advances needed to combat ALS in the third millennium.