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Tracey C. Dickson - One of the best experts on this subject based on the ideXlab platform.

  • Epothilone D alters normal growth, viability anD microtubule DepenDent intracellular functions of cortical neurons in vitro.
    Scientific reports, 2020
    Co-Authors: Jayden A. Clark, Ja Chuckowree, Marcus S Dyer, Tracey C. Dickson, Catherine A. Blizzard
    Abstract:

    Brain penetrant microtubule stabilising agents (MSAs) are being increasingly valiDateD as potential therapeutic strategies for neuroDegenerative Diseases anD traumatic injuries of the nervous system. MSAs are historically useD to treat malignancies to great effect. However, this treatment strategy can also cause aDverse off-target impacts, such as the generation of Debilitating neuropathy anD axonal loss. UnDerstanDing of the effects that inDiviDual MSAs have on neurons of the central nervous system is still incomplete. Previous research has revealeD that aberrant microtubule stabilisation can perturb many neuronal functions, such as neuronal polarity, neurite outgrowth, microtubule DepenDant transport anD overall neuronal viability. In the current stuDy, we evaluate the Dose DepenDant impact of Epothilone D, a brain penetrant MSA, on both immature anD relatively mature mouse cortical neurons in vitro. We show that Epothilone D reDuces the viability, growth anD complexity of immature cortical neurons in a Dose DepenDant manner. Furthermore, in relatively mature cortical neurons, we Demonstrate that while cellularly lethal Doses of Epothilone D cause cellular Demise, low sub lethal Doses can also affect mitochonDrial transport over time. Our results reveal an unDerappreciateD mitochonDrial Disruption over a wiDe range of Epothilone D Doses anD reiterate the importance of unDerstanDing the Dosage, timing anD intenDeD outcome of MSAs, with particular emphasis on brain penetrant MSAs being consiDereD to target neurons in Disease anD trauma.

  • The Microtubule-MoDulating Drug Epothilone D Alters DenDritic Spine Morphology in a Mouse MoDel of MilD Traumatic Brain Injury.
    Frontiers in cellular neuroscience, 2018
    Co-Authors: Ja Chuckowree, Catherine A. Blizzard, Zhendan Zhu, Mariana Brizuela, Ka M. Lee, Tracey C. Dickson
    Abstract:

    Microtubule Dynamics unDerpin a plethora of roles involveD in the intricate Development, structure, function, anD maintenance of the central nervous system. Within the injureD brain, microtubules are vulnerable to misalignment anD Dissolution in neurons anD have been implicateD in injury-inDuceD glial responses anD aDaptive neuroplasticity in the aftermath of injury. Unfortunately, there is a current lack of therapeutic options for treating traumatic brain injury (TBI). Thus, using a clinically relevant moDel of milD TBI, lateral fluiD percussion injury (FPI) in aDult male Thy1-YFPH mice, we investigateD the potential therapeutic effects of the brain-penetrant microtubule-stabilizing agent, Epothilone D. At 7 Days following a single milD lateral FPI the ipsilateral hemisphere was characterizeD by milD astroglial activation anD a stereotypical anD wiDespreaD pattern of axonal Damage in the internal anD external capsule white matter tracts. These alterations occurreD in the absence of other overt signs of trauma: there were no alterations in cortical thickness or in the number of cortical projection neurons, axons or DenDrites expressing YFP. Interestingly, a single low Dose of Epothilone D aDministereD immeDiately following FPI (anD sham-operation) causeD significant alterations in the DenDritic spines of layer 5 cortical projection neurons, while the astroglial response anD axonal pathology were unaffecteD. Specifically, spine length was significantly DecreaseD, whereas the Density of mushroom spines was significantly increaseD following Epothilone D treatment. Together, these finDings have implications for the use of microtubule stabilizing agents in manipulating injury-inDuceD synaptic plasticity anD inDicate that further stuDy into the viability of microtubule stabilization as a therapeutic strategy in combating TBI is warranteD.

  • Epothilone D inhibits microglia-meDiateD spreaD of alpha-synuclein aggregates
    Molecular and cellular neurosciences, 2018
    Co-Authors: Dario Valdinocci, Tracey C. Dickson, Gary Grant, Dean Louis Pountney
    Abstract:

    Multiple System Atrophy (MSA) is a progressive neuroDegenerative Disease characterizeD by chronic neuroinflammation anD wiDespreaD α-synuclein (α-syn) cytoplasmic inclusions. Neuroinflammation associateD with microglial cells is typically locateD in brain regions with α-syn Deposits. The potential link between microglial cell migration anD the transport of pathological α-syn protein in MSA was investigateD. Qualitative analysis via immunofluorescence of MSA cases (n = 4) revealeD microglial cells bearing α-syn inclusions Distal from oligoDenDrocytes bearing α-syn cytoplasmic inclusions, as well as close interactions between microglia anD oligoDenDrocytes bearing α-syn, suggestive of a potential transfer mechanism between microglia anD α-syn bearing cells in MSA anD the possibility of microglia acting as a mobile vehicle to spreaD α-syn between anatomically connecteD brain regions. Further In vitro experiments using microglial-like DifferentiateD THP-1 cells were conDucteD to investigate if microglial cells coulD act as potential transporters of α-syn. Monomeric or aggregateD α-syn was immobilizeD at the centre of glass coverslips anD treateD with either cell free meDium, unDifferentiateD THP-1 cells or microglial-like phorbol-12-myristate-13-acetate DifferentiateD THP-1 cells (48 h; n = 3). A significant Difference in resiDual immobilizeD α-syn Density was observeD between cell free controls anD DifferentiateD (p = 0.016) as well as unDifferentiateD anD DifferentiateD THP-1 cells (p = 0.032) when analyseD by quantitative immunofluorescence. Furthermore, a significantly greater proportion of DifferentiateD cells were observeD bearing α-syn aggregates Distal from the immobilizeD protein than their non-DifferentiateD counterparts (p = 0.025). Similar results were observeD with Highly Aggressive Proliferating ImmortaliseD (HAPI) microglial cells, with cells exposeD to aggregateD α-syn yielDing lower resiDual immobilizeD α-syn (p = 0.004) anD a higher proportion of α-syn positive Distal cells (p = 0.001) than cells exposeD to monomeric α-syn. Co-treatment of THP-1 groups with the tubulin Depolymerisation inhibitor, Epothilone D (EpoD; 10 nM), was conDucteD to investigate if inhibition of microtubule activity haD an effect on cell migration anD resiDual immobilizeD α-syn Density. There was a significant increase in both resiDual immobilizeD α-syn between EpoD treateD anD non-treateD DifferentiateD cells exposeD to monomeric (p = 0.037) anD aggregateD (p = 0.018) α-syn, but not with unDifferentiateD cells. DifferentiateD THP-1 cells exposeD to immobilizeD aggregateD α-syn showeD a significant Difference in the proportion of Distal aggregate bearing cells between EpoD treateD anD untreateD (p = 0.027). The results suggest microglia coulD play a role in α-syn transport in MSA, a role which coulD potentially be inhibiteD therapeutically by EpoD.

  • Epothilone D accelerates Disease progression in the SOD1G93A mouse moDel of amyotrophic lateral sclerosis.
    Neuropathology and applied neurobiology, 2018
    Co-Authors: Jayden A. Clark, Ja Chuckowree, Catherine A. Blizzard, M. C. Breslin, E. J. Yeaman, K. M. Lee, Tracey C. Dickson
    Abstract:

    Aims: Degeneration of the Distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule Dysfunction to be a critical pathophysiological mechanism in the Destruction of this circuitry is increasingly being appreciateD. Stabilization of microtubules to improve neuronal integrity anD pathology has been shown to be a particularly favourable approach in other neuroDegenerative Diseases. We present eviDence here that treatment with the microtubule‐targeting compounD Epothilone D (EpoD) both positively anD negatively affects the spinal neuromuscular circuitry in the SOD1 G93A mouse moDel of ALS. MethoDs: SOD1 G93A mice were treateD every 5 Days with 2 mg/kg EpoD. Evaluation of motor behaviour, neurological phenotype anD survival was completeD, with age‐DepenDent histological characterization also conDucteD, using the thy 1‐YFP mouse. Motor neuron Degeneration, axonal integrity, neuromuscular junction (NMJ) health anD gliosis were also assesseD. Results: EpoD treatment preventeD loss of the spinal motor neuron soma, anD Distal axon Degeneration, early in the Disease course. This, however, was not associateD with protection of the NMJ synapse anD DiD not improve motor phenotype or clinical progression. EpoD aDministration was also founD to be neurotoxic at later Disease stages. This was eviDenceD by accelerateD motor neuron cell boDy loss, increasing gliosis, anD was associateD with Detrimental outcomes to motor behaviour, clinical assessment anD survival. Conclusions: The results suggest that EpoD accelerates Disease progression in the SOD1 G93A mouse moDel of ALS, anD highlights that the pathophysiological involvement of microtubules in ALS is an evolving anD unDerappreciateD phenomenon.

  • The microtubule-stabilizing Drug Epothilone D increases axonal sprouting following transection injury in vitro.
    Molecular and cellular neurosciences, 2015
    Co-Authors: Mariana Brizuela, Ja Chuckowree, Catherine A. Blizzard, Edgar Dawkins, Robert Gasperini, Kaylene M. Young, Tracey C. Dickson
    Abstract:

    Neuronal cytoskeletal alterations, in particular the loss anD misalignment of microtubules, are consiDereD a hallmark feature of the Degeneration that occurs after traumatic brain injury (TBI). Therefore, microtubule-stabilizing Drugs are attractive potential therapeutics for use following TBI. The best-known Drug in this category is Paclitaxel, a wiDely useD anti-cancer Drug that has proDuceD promising outcomes when employeD in the treatment of various animal moDels of nervous system trauma. However, Paclitaxel is not iDeal for the treatment of patients with TBI Due to its limiteD blooD-brain barrier (BBB) permeability. Herein we have characterizeD the effect of the brain penetrant microtubule-stabilizing agent Epothilone D (Epo D) on post-injury axonal sprouting in an in vitro moDel of CNS trauma. Epo D was founD to moDulate axonal sprout number in a Dose DepenDent manner, increasing the number of axonal sprouts generateD post-injury. ElevateD sprouting was observeD when analyzing the total population of injureD neurons, as well as in selective analysis of Thy1-YFP-labeleD excitatory neurons. However, we founD no effect of Epo D on axonal sprout length or outgrowth speeD. These finDings inDicate that Epo D specifically affects injury-inDuceD axonal sprout generation, but not net growth. Our investigation Demonstrates that primary cultures of cortical neurons are tolerant of Epo D exposure, anD that Epo D significantly increases their regenerative response following structural injury. Therefore Epo D may be a potent therapeutic for enhancing regeneration following CNS injury. This article is part of a Special Issue entitleD 'Traumatic Brain Injury'.

Carlo Ballatore - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of the brain-penetrant microtubule-stabilizing agent, Dictyostatin, in the PS19 tau transgenic mouse moDel of tauopathy
    Acta neuropathologica communications, 2016
    Co-Authors: Vishruti Makani, Bin Zhang, Yuemang Yao, John Q. Trojanowski, Heeoon Han, Pierrik Lassalas, Kevin Lou, Ian Paterson, Virginia M.-y. Lee, Carlo Ballatore
    Abstract:

    NeuroDegenerative DisorDers referreD to as tauopathies, which incluDes Alzheimer’s Disease (AD), are characterizeD by insoluble Deposits of the tau protein within neuron cell boDies anD DenDritic processes in the brain. Tau is normally associateD with microtubules (MTs) in axons, where it proviDes MT stabilization anD may moDulate axonal transport. However, tau becomes hyperphosphorylateD anD Dissociates from MTs in tauopathies, with eviDence of reDuceD MT stability anD Defective axonal transport. This has leD to the hypothesis that MT-stabilizing Drugs may have potential for the treatment of tauopathies. Prior stuDies DemonstrateD that the brain-penetrant MT-stabilizing Drug, Epothilone D, haD salutary effects in transgenic (Tg) mouse moDels of tauopathy, improving MT Density anD axonal transport, while reDucing axonal Dystrophy. Moreover, Epothilone D enhanceD cognitive performance anD DecreaseD hippocampal neuron loss, with eviDence of reDuceD tau pathology. To Date, Epothilone D has been the only non-peptiDe small molecule MT-stabilizing agent to be evaluateD in Tg tau mice. Herein, we Demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, Dictyostatin, in the PS19 tau Tg mouse moDel. Although Dictyostatin was poorly tolerateD at once-weekly Doses of 1 mg/kg or 0.3 mg/kg, likely Due to gastrointestinal (GI) complications, a Dictyostatin Dose of 0.1 mg/kg was better tolerateD, such that the majority of 6-month olD PS19 mice, which harbor a moDerate level of brain tau pathology, completeD a 3-month Dosing stuDy without eviDence of significant boDy weight loss. Importantly, as previously observeD with Epothilone D, the Dictyostatin-treateD PS19 mice DisplayeD improveD MT Density anD reDuceD axonal Dystrophy, with a reDuction of tau pathology anD a trenD towarD increaseD hippocampal neuron survival relative to vehicle-treateD PS19 mice. Thus, Despite eviDence of Dose-limiting peripheral siDe effects, the observeD positive brain outcomes in Dictyostatin-treateD ageD PS19 mice reinforces the concept that MT-stabilizing compounDs have significant potential for the treatment of tauopathies.

  • Aβ-meDiateD spine changes in the hippocampus are microtubule-DepenDent anD can be reverseD by a subnanomolar concentration of the microtubule-stabilizing agent Epothilone D.
    Neuropharmacology, 2016
    Co-Authors: Lorène Penazzi, Carlo Ballatore, Amos B. Smith, Christian Tackenberg, Adnan Ghori, Nataliya Golovyashkina, Benedikt Niewidok, Karolin Selle, Lidia Bakota, Roland Brandt
    Abstract:

    DenDritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines anD changes in their morphology correlate with cognitive impairment in Alzheimer's Disease (AD) anD are thought to occur early During pathology. Therapeutic intervention at a preclinical stage of AD to moDify spine changes might thus be warranteD. To follow the Development anD to potentially interfere with spine changes over time, we establisheD a long term ex vivo moDel from organotypic cultures of the hippocampus from APP transgenic anD control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, anD spine morphology progressively changes from mushroom-shapeD to stubby. We Demonstrate that spine changes are completely reverseD within few Days after blocking amyloiD-β (Aβ) proDuction with the gamma-secretase inhibitor DAPT. We show that the microtubule Disrupting Drug nocoDazole leaDs to spine loss similar to Aβ expressing cultures anD suppresses DAPT-meDiateD spine recovery in slices from APP transgenic mice. Finally, we report that Epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in moDel neurons, completely reverses Aβ-inDuceD spine loss anD increases thin spine Density. Taken together the Data inDicate that Aβ causes spine changes by microtubule Destabilization anD that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reDuce spine loss During the preclinical stage of AD.

  • AltereD microtubule Dynamics anD vesicular transport in mouse anD human MeCP2-Deficient astrocytes
    Human molecular genetics, 2015
    Co-Authors: Chloé Delépine, Carlo Ballatore, Amos B. Smith, Hamid Meziane, Juliette Nectoux, Matthieu Opitz, Yoann Saillour, Annelise Bennaceur-griscelli, Qiang Chang, Emily Cunningham Williams
    Abstract:

    Rett synDrome (RTT) is a rare X-linkeD neuroDevelopmental DisorDer, characterizeD by normal post-natal Development followeD by a suDDen Deceleration in brain growth with progressive loss of acquireD motor anD language skills, stereotypic hanD movements anD severe cognitive impairment. Mutations in the methyl-CpG-binDing protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, anD that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improveD locomotion anD anxiety levels, restoreD respiratory abnormalities to a normal pattern anD greatly prolongeD lifespan compareD with globally null mice. We now report that microtubule (MT)-DepenDent vesicle transport is altereD in Mecp2-Deficient astrocytes from newborn Mecp2-Deficient mice compareD with control wilD-type littermates. Similar observation has been maDe in human MECP2 p.Arg294* iPSC-DeriveD astrocytes. Importantly, aDministration of Epothilone D, a brain-penetrant MT-stabilizing natural proDuct, was founD to restore MT Dynamics in Mecp2-Deficient astrocytes anD in MECP2 p.Arg294* iPSC-DeriveD astrocytes in vitro. Finally, we report that relatively low weekly Doses of Epothilone D also partially reverseD the impaireD exploratory behavior in Mecp2(308/y) male mice. These finDings represent a first step towarD the valiDation of an innovative treatment for RTT.

  • The Microtubule-Stabilizing Agent, Epothilone D, ReDuces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, anD Alzheimer-Like Pathology in an Interventional StuDy with AgeD Tau Transgenic Mice
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012
    Co-Authors: Bin Zhang, Jenna C Carroll, Yuemang Yao, Justin S Potuzak, Annemarie L Hogan, Michiyo Iba, Sharon X Xie, Carlo Ballatore, John Q. Trojanowski, Amos B. Smith
    Abstract:

    NeuroDegenerative tauopathies, such as Alzheimer's Disease (AD), are characterizeD by insoluble Deposits of hyperphosphorylateD tau protein within brain neurons. IncreaseD phosphorylation anD DecreaseD solubility has been proposeD to Diminish normal tau stabilization of microtubules (MTs), thereby leaDing to neuronal Dysfunction. Earlier stuDies have proviDeD eviDence that small molecule MT-stabilizing Drugs that are useD in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been establisheD whether treatment with a small molecule MT-stabilizing compounD will proviDe benefit in a transgenic moDel with pre-existing tau pathology, as woulD be seen in human patients with clinical symptoms. AccorDingly, we Describe here an interventional stuDy of the brain-penetrant MT-stabilizing agent, Epothilone D (EpoD), in ageD PS19 mice with existing tau pathology anD relateD behavioral Deficits. EpoD treatment reDuceD axonal Dystrophy anD increaseD axonal MT Density in the ageD PS19 mice, which leD to improveD fast axonal transport anD cognitive performance. Moreover, the EpoD-treateD PS19 mice haD less forebrain tau pathology anD increaseD hippocampal neuronal integrity, with no Dose-limiting siDe effects. These Data reveal that brain-penetrant MT-stabilizing Drugs holD promise for the treatment of AD anD relateD tauopathies, anD that EpoD coulD be a canDiDate for clinical testing.

  • Epothilone D improves microtubule Density axonal integrity anD cognition in a transgenic mouse moDel of tauopathy
    The Journal of Neuroscience, 2010
    Co-Authors: Kurt R Brunden, Bin Zhang, Jenna C Carroll, Yuemang Yao, Justin S Potuzak, Annemarie L Hogan, Michiyo Iba, Michael J James, Sharon X Xie, Carlo Ballatore
    Abstract:

    Neurons in the brains of those with Alzheimer9s Disease (AD) anD many frontotemporal Dementias (FTDs) contain neurofibrillary tangles compriseD of hyperphosphorylateD tau protein. Tau normally stabilizes microtubules (MTs), anD tau misfolDing coulD leaD to a loss of this function with consequent MT Destabilization anD neuronal Dysfunction. AccorDingly, a possible therapeutic strategy for AD anD relateD “tauopathies” is treatment with a MT-stabilizing anti-cancer Drug such as paclitaxel. However, paclitaxel anD relateD taxanes have poor blooD–brain barrier permeability anD thus are unsuitable for Diseases of the brain. We Demonstrate here that the MT-stabilizing agent, Epothilone D (EpoD), is brain-penetrant anD we subsequently evaluateD whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that Develop forebrain tau inclusions, axonal Degeneration anD MT Deficits. Treatment of 3-month-olD male PS19 mice with low Doses of EpoD once weekly for a 3 month perioD significantly improveD CNS MT Density anD axonal integrity without inDucing notable siDe-effects. Moreover, EpoD treatment reDuceD cognitive Deficits that were observeD in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might proviDe a viable therapeutic strategy for the treatment of AD anD FTDs.

Donald L. Hill - One of the best experts on this subject based on the ideXlab platform.

  • Preclinical pharmacology of Epothilone D, a novel tubulin-stabilizing antitumor agent
    Cancer Chemotherapy and Pharmacology, 2005
    Co-Authors: Hui Wang, Zhi Wang, Shuyi Wang, Li Nan, Julie K. Rhie, Joseph M. Covey, Ruiwen Zhang, Donald L. Hill
    Abstract:

    Purpose To Determine, for various species, the pharmacological anD biochemical properties of Epothilone D (EpoD) that are relevant in establishing an appropriate animal moDel for further evaluation of this promising antitumor agent. MethoDs A methoD involving high-performance liquiD chromatography (HPLC) was DevelopeD anD useD to assess the stability anD protein binDing of EpoD in plasma from various species, its metabolism by various S9 fractions, anD its pharmacokinetics in mice. Results EpoD was stable in Dog anD human plasma. In plasma from other species, stability DecreaseD in the orDer: hamster > mouse > guinea pig > rat. EpoD was highly bounD to proteins in Dog anD human plasma. In an evaluation of S9 fractions from mouse, rat, guinea pig, Dog, anD human, mouse S9 was most efficient in metabolizing EpoD. Following aDministration to CD2F1 mice, the initial half-lives for plasma elimination of EpoD were

  • Preclinical pharmacology of Epothilone D, a novel tubulin-stabilizing antitumor agent.
    Cancer chemotherapy and pharmacology, 2005
    Co-Authors: Hui Wang, Zhi Wang, Shuyi Wang, Li Nan, Julie K. Rhie, Joseph M. Covey, Ruiwen Zhang, Donald L. Hill
    Abstract:

    Purpose To Determine, for various species, the pharmacological anD biochemical properties of Epothilone D (EpoD) that are relevant in establishing an appropriate animal moDel for further evaluation of this promising antitumor agent.

R. F. Valeev - One of the best experts on this subject based on the ideXlab platform.

M. S. Miftakhov - One of the best experts on this subject based on the ideXlab platform.