Repositioning Microtubule Stabilizing Drugs for Brain Disorders

Microtubule stabilizing agents are among the most clinically useful chemotherapeutic drugs. Mostly, they act to stabilize microtubules and inhibit cell division. While not without side effects, new generations of these compounds display improved pharmacokinetic properties and brain penetrance. Neurological disorders are intrinsically associated with microtubule defects, and efforts to reposition microtubule-targeting chemotherapeutic agents for treatment of neurodegenerative and psychiatric illnesses are underway. Here we catalog microtubule regulators that are associated with Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia and mood disorders. We outline the classes of microtubule stabilizing agents used for cancer treatment, their brain penetrance properties and neuropathy side effects, and describe efforts to apply these agents for treatment of brain disorders. Finally, we summarize the current state of clinical trials for microtubule stabilizing agents under evaluation for central nervous system disorders.

• Publication year

  2018

• Venue

  Frontiers in Cellular Neuroscience

• Publication date

  2018-08-08

• Fields of study

  Medicine

• Identifiers
  DOI 10.3389/fncel.2018.00226PMID 30135644PMCID 6092511
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.

  2019cited by this paper
• Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats

  2018cited by this paper
• Epothilone D accelerates disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

  2018cited by this paper
• ADNP, a Microtubule Interacting Protein, Provides Neuroprotection Through End Binding Proteins and Tau: An Amplifier Effect

  2018cited by this paper
• Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children

  2017cited by this paper
• Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis

  2017cited by this paper
• Spatial‐specific functions in retrograde neuronal signalling

  2017cited by this paper
• Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin.

  2017cited by this paper
• ADNP/NAP dramatically increase microtubule end-binding protein–Tau interaction: a novel avenue for protection against tauopathy

  2017cited by this paper
• Propagation of Tau Aggregates and Neurodegeneration.

  2017cited by this paper
• Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration.

  2017cited by this paper
• 3D imaging of the brain morphology and connectivity defects in a model of psychiatric disorders: MAP6-KO mice

  2017cited by this paper
• ADNP Plays a Key Role in Autophagy: From Autism to Schizophrenia and Alzheimer's Disease

  2017cited by this paper
• Meta-analysis of the association between variants in MAPT and neurodegenerative diseases

  2017cited by this paper
• Cabazitaxel operates anti-metastatic and cytotoxic via apoptosis induction and stalls brain tumor angiogenesis

  2016cited by this paper
• Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination

  2016cited by this paper
• Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer’s Disease and Related Tauopathies

  2016cited by this paper
• Microtubule and microtubule associated protein anomalies in psychiatric disease

  2016influential reference
• Erratum to: Rectocutaneous fistula with transmigration of the suture: a rare delayed complication of vault fixation with the sacrospinous ligament

  2016cited by this paper
• 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.

  2016cited by this paper
• Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory

  2016cited by this paper
• Antidepressant effect of recombinant NT4-NAP/AAV on social isolated mice through intranasal route

  2016cited by this paper
• Microtubules in health and degenerative disease of the nervous system.

  2016cited by this paper
• Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation-dependent mechanism

  2016cited by this paper
• A phase I study of TPI 287 in combination with temozolomide for patients with metastatic melanoma

  2016cited by this paper
• Epothilone D prevents binge methamphetamine‐mediated loss of striatal dopaminergic markers

  2016cited by this paper
• The genetic landscape of Alzheimer disease: clinical implications and perspectives

  2015cited by this paper
• Systemic administration of epothilone B promotes axon regeneration after spinal cord injury

  2015cited by this paper
• Improved anti-glioblastoma efficacy by IL-13Rα2 mediated copolymer nanoparticles loaded with paclitaxel

  2015cited by this paper
• Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer’s Disease Biomarkers

  2015cited by this paper
• Efficacy of cabazitaxel in mouse models of pediatric brain tumors.

  2015cited by this paper
• Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model

  2015cited by this paper
• Transport

  2015cited by this paper
• Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.

  2015cited by this paper
• The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins

  2014cited by this paper
• A SWI/SNF related autism syndrome caused by de novo mutations in ADNP

  2014cited by this paper
• New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia

  2014cited by this paper
• High-resolution microtubule structures reveal the structural transitions in αβ-tubulin upon GTP hydrolysis.

  2014cited by this paper
• Development of other microtubule-stabilizer families: the epothilones and their derivatives

  2014cited by this paper
• Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α-synuclein

  2014cited by this paper
• Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer’s Disease and Related Tauopathies

  2014cited by this paper
• LIS1 functions in normal development and disease.

  2013cited by this paper
• MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications.

  2013cited by this paper
• Autophagy has a key role in the pathophysiology of schizophrenia

  2013cited by this paper
• A Double-Blind, Placebo-Controlled, Ascending-Dose, Randomized Study to Evaluate the Safety, Tolerability and Effects on Cognition of AL-108 after 12 Weeks of Intranasal Administration in Subjects with Mild Cognitive Impairment

  2013cited by this paper
• Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects

  2013cited by this paper
• Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia

  2013cited by this paper
• Microtubule Alterations Occur Early in Experimental Parkinsonism and The Microtubule Stabilizer Epothilone D Is Neuroprotective

  2013cited by this paper
• NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.

  2013cited by this paper
• NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy

  2013cited by this paper
• The impact of cancer therapy on cognition in the elderly

  2013cited by this paper
• The ADNP Derived Peptide, NAP Modulates the Tubulin Pool: Implication for Neurotrophic and Neuroprotective Activities

  2012cited by this paper
• TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

  2012cited by this paper
• The deletion of STOP/MAP6 protein in mice triggers highly altered mood and impaired cognitive performances

  2012cited by this paper
• Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia.

  2012cited by this paper
• Reduced Expression of STOP/MAP6 in Mice Leads to Cognitive Deficits

  2012cited by this paper
• Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial.

  2012cited by this paper
• 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

  2012cited by this paper
• Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

  2012cited by this paper
• DNA Repair Genes in Parkinson's Disease

  2012cited by this paper
• Safety, Pharmacokinetics, and Activity of GRN1005, a Novel Conjugate of Angiopep-2, a Peptide Facilitating Brain Penetration, and Paclitaxel, in Patients with Advanced Solid Tumors

  2011cited by this paper
• Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE

  2011cited by this paper
• Activity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: deregulation in schizophrenia.

  2011cited by this paper
• Molecular Genetics of Neuronal Migration Disorders

  2011cited by this paper
• A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions.

  2011cited by this paper
• Cyclin-dependent kinase 5 activator p25 is generated during memory formation and is reduced at an early stage in Alzheimer's disease.

  2011cited by this paper
• The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.

  2011cited by this paper
• A phase II study of sagopilone (ZK 219477; ZK-EPO) in patients with breast cancer and brain metastases.

  2011cited by this paper
• Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities

  2010cited by this paper
• NAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse--a microtubule-deficient model of schizophrenia.

  2010cited by this paper
• Chemotherapy-induced peripheral neurotoxicity

  2010cited by this paper
• Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia.

  2010cited by this paper
• Tau in Alzheimer disease and related tauopathies.

  2010cited by this paper
• Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.

  2010cited by this paper
• The Neuroprotective Peptide NAP Does Not Directly Affect Polymerization or Dynamics of Reconstituted Neural Microtubules

  2010cited by this paper
• Altered expression of glutamate signaling, growth factor and glia genes in the locus coeruleus of patients with major depression

  2010cited by this paper
• Alpha- and Beta-Synucleins mRNA Expression in Lymphocytes of Schizophrenia Patients

  2010cited by this paper
• Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy

  2010cited by this paper
• Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding

  2009cited by this paper
• Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases.

  2009cited by this paper
• Addressing Alzheimer's disease tangles: from NAP to AL-108.

  2009cited by this paper
• Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease

  2009cited by this paper
• Genomic convergence to identify candidate genes for Alzheimer Disease on chromosome 10

  2009cited by this paper
• Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.

  2009cited by this paper
• Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer's Disease

  2009cited by this paper
• A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

  2008cited by this paper
• Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep‐2

  2008cited by this paper
• Dual‐specificity tyrosine(Y)‐phosphorylation regulated kinase 1A‐mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease

  2008cited by this paper
• The role of the cytoskeleton during neuronal polarization.

  2008cited by this paper
• TTI-237: a novel microtubule-active compound with in vivo antitumor activity.

  2008cited by this paper
• Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule.

  2007cited by this paper
• BRCA1 May Modulate Neuronal Cell Cycle Re-Entry in Alzheimer Disease

  2007cited by this paper
• The Tubulin Code

  2007cited by this paper
• Activity-dependent Neuroprotective Protein Constitutes a Novel Element in the SWI/SNF Chromatin Remodeling Complex*

  2007cited by this paper
• Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model.

  2007cited by this paper
• BRCA1 regulates γ-tubulin binding to centrosomes

  2007cited by this paper
• BRCA1 regulates gamma-tubulin binding to centrosomes.

  2007cited by this paper
• Down‐regulation of cAMP‐dependent protein kinase by over‐activated calpain in Alzheimer disease brain

  2007cited by this paper
• NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP).

  2006cited by this paper
• Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.

  2006cited by this paper

• Microarray analysis for transcriptomic profiling in neuroscience: uncovering key molecular mechanisms and candidate biomarkers in Alzheimer’s disease

  2026cites this paper
• Brain-penetrant microtubule-stabilizer epothilone B delays isoflurane-induced unconsciousness in mice.

  2026cites this paper
• An Expedient Synthesis of the Antimitotic Natural Products Sarcodictyin and Eleutherobin, and Carbohydrate Analogues.

  2025cites this paper
• Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

  2025cites this paper
• NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights

  2025cites this paper
• Imaging microtubule dynamics: A new frontier in biomarker development for neurodegenerative diseases

  2025cites this paper
• Cellular and proteomic differences associated with lithium response in olfactory neuroepithelium cells of bipolar disorder patients

  2025cites this paper
• Interplay Between Aging and Tau Pathology in Alzheimer’s Disease: Mechanisms and Translational Perspectives

  2025cites this paper
• Progress on the functions and mechanisms of natural products in anti-glioma therapy.

  2025cites this paper
• A review: From old drugs to new solutions: The role of repositioning in alzheimer's disease treatment.

  2025cites this paper
• Newer Therapeutic Approaches in Treating Alzheimer’s Disease: A Comprehensive Review

  2025cites this paper
• Diversity of microtubule arrays in animal cells at a glance.

  2025cites this paper
• Computational discovery of potential therapeutic agents against brain-eating amoeba (Naegleria fowleri)

  2025cites this paper
• Cytoskeleton-modulating nanomaterials and their therapeutic potentials.

  2024cites this paper
• Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets

  2024cites this paper
• Potential benefits of marine-derived compounds for slowing the advancement of Alzheimer’s disease

  2024cites this paper
• Microtubule-Stabilizer Epothilone B Delays Anesthetic-Induced Unconsciousness in Rats

  2024cites this paper
• Neuronal ageing is promoted by the decay of the microtubule cytoskeleton

  2024cites this paper
• Structural insights into the mechanism of GTP initiation of microtubule assembly

  2023cites this paper
• Microtubule stabilising peptides: new paradigm towards management of neuronal disorders.

  2023cites this paper
• Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer’s Disease via Gut Microbiome

  2023cites this paper
• Cellular cartography: Towards an atlas of the neuronal microtubule cytoskeleton

  2023cites this paper
• Alzheimer’s Disease Related Target and Therapies

  2023cites this paper
• Bioinformatic prediction of the molecular links between Alzheimer’s disease and diabetes mellitus

  2023cites this paper
• Microtubule decay is a driver of neuronal ageing and a promising target for intervention

  2023influential citation
• Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

  2023cites this paper
• Microtubules as Regulators of Neural Network Shape and Function: Focus on Excitability, Plasticity and Memory

  2022cites this paper
• Role of structural components of the 2-methoxyestradiol—chlorambucil conjugate in microtubule stabilization

  2022cites this paper
• Collection of Hairy Roots as a Basis for Fundamental and Applied Research

  2022cites this paper
• The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection

  2022cites this paper
• Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease

  2022cites this paper
• Rational Discovery of Microtubule-Stabilizing Peptides

  2022cites this paper
• Farnesyltransferase inhibitor LNK-754 attenuates axonal dystrophy and reduces amyloid pathology in mice

  2022cites this paper
• Radiosynthesis and evaluation of [11C]AG-488, a dual anti-angiogenetic and anti-tubulin PET ligand.

  2022cites this paper
• Manganese-enhanced magnetic resonance imaging method detects age-related impairments in axonal transport in mice and attenuation of the impairments by a microtubule-stabilizing compound.

  2022cites this paper
• New frontier radioiodinated probe based on in silico resveratrol repositioning for microtubules dynamic targeting

  2022cites this paper
• Virus-Induced Membrane Fusion in Neurodegenerative Disorders

  2022cites this paper
• Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models

  2022influential citation
• Tubulin/microtubules as novel clozapine targets

  2021cites this paper
• Cytoskeletal proteins as glioblastoma biomarkers and targets for therapy: a systematic review.

  2021cites this paper
• Pathogenic MAPT mutations Q336H and Q336R have isoform‐dependent differences in aggregation propensity and microtubule dysfunction

  2021cites this paper
• Intranasal Paclitaxel Alters Alzheimer’s Disease Phenotypic Features in 3xTg-AD Mice

  2021cites this paper
• Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

  2021cites this paper
• Improving motor neuron-like cell differentiation of hEnSCs by the combination of epothilone B loaded PCL microspheres in optimized 3D collagen hydrogel

  2021cites this paper
• Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

  2021cites this paper
• Advances in Genetics and Epigenetic Alterations in Alzheimer’s Disease: A Notion for Therapeutic Treatment

  2021cites this paper
• Microtubule Integrity Is Associated with the Functional Activity of Mitochondria in HEK293

  2021cites this paper
• A Role of Microtubules in Oligodendrocyte Differentiation

  2020cites this paper
• Cell Biology International

  2020cites this paper
• Disease-modifying therapies in amyotrophic lateral sclerosis.

  2020cites this paper
• Epothilones Improve Axonal Growth and Motor Outcomes after Stroke in the Adult Mammalian CNS

  2020cites this paper
• Investigation of low dose cabazitaxel potential as microtubule stabilizer in experimental model of Alzheimer's disease: Restoring neuronal cytoskeleton.

  2020cites this paper
• Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications.

  2020cites this paper
• Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

  2020cites this paper
• Title: CCP1, a tubulin deglutamylase, increases survival of rodent spinal cord neurons following glutamate-induced excitotoxicity Abbreviated title: CCP1 supports neuronal survival of excitotoxicity

  2020cites this paper
• CCP1, a Tubulin Deglutamylase, Increases Survival of Rodent Spinal Cord Neurons following Glutamate-Induced Excitotoxicity

  2020cites this paper
• Alzheimer's disease: Recent treatment strategies.

  2020cites this paper
• Heterologous redox partners supporting the efficient catalysis of epothilone B biosynthesis by EpoK in Schlegelella brevitalea

  2020cites this paper
• Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model

  2020cites this paper
• Tackling Alzheimer's Disease with Existing Drugs: Playing Dirty for Bypassing Obstacles.

  2020cites this paper
• Reassembly of the biosynthetic gene cluster enables high epothilone yield in engineered Schlegelella brevitalea.

  2020cites this paper
• Targeting Axonal Transport: A New Therapeutic Avenue for ALS

  2020cites this paper
• Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity

  2020cites this paper
• Targeting Tau to Treat Clinical Features of Huntington's Disease

  2020cites this paper
• Altered Circadian Activity and Sleep/Wake Rhythms in the Stable Tubule Only Polypeptide (STOP) Null Mouse Model of Schizophrenia.

  2020cites this paper
• Overview of novel multifunctional agents based on conjugates of γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes for treatment of Alzheimer's disease.

  2019cites this paper
• A study of the behavioral, anatomical, metabolic and transcriptomic disturbances associated to cocaine addiction-like behaviour in a two-hit animal model of schizophrenia-related symptoms

  2019cites this paper
• Synthesis and Evaluation of a Metabolically Stabilized Analog and Conjugates of Pironetin

  2019cites this paper
• C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES

  2019cites this paper
• In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands.

  2019cites this paper
• Potential use of edaravone to reduce specific side effects of chemo-, radio- and immuno-therapy of cancers.

  2019cites this paper
• Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

  2019cites this paper
• Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

  2019cites this paper
• Revisiting microtubule targeting agents: α-Tubulin and the pironetin binding site as unexplored targets for cancer therapeutics.

  2019cites this paper
• Power of Tyrosine Assembly in Microtubule Stabilization and Neuroprotection Fueled by Phenol Appendages.

  2019cites this paper
• Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis

  2017cites this paper
• Antidepressant effect of recombinant NT4-NAP/AAV on social isolated mice through intranasal route

  2016cites this paper