Advertisement

Management of HD: Insight into Molecular Mechanisms and Potential Neuroprotective Drug Strategies

  • Puneet Kumar
  • Sumit Jamwal
  • Anil Kumar
Chapter

Abstract

Huntington’s disease (HD) is a rare type of hyperkinetic and neurodegenerative disorder characterized by abnormalities in cognitive, behavioral, and motor system, associated with picky degeneration of GABAergic medium spiny neurons (MSNs) in basal ganglia. HD results from an unhinged expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. Emerging strides have enabled us to understand the role of various pathogenic mechanisms like oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, apoptosis, transcriptional dysregulation and ubiquitin-proteasome pathway dysregulation by mutant huntingtin protein (mHTT) in HD. Presently, treatment of HD is symptomatic in nature, without targeting any specific neurodegenerative processes. In particular, genetic and toxin based HD experimental animal/models have been helpful in studying the sequence of neurodegeneration in HD. Abovementioned molecular mechanism implicated in the pathophysiology of HD presents valuable future therapeutic targets. The apparent or traditional approach of treating HD subjects with antioxidants and anti-inflammatory agents is beneficial in well-established various toxin and genetic models with considerable positive results to some extent. However, these findings could not be effectively translated to clinical practice as use of antioxidants and anti-inflammatory agents met with limited success, highlighting several limitations to these approaches. Therefore, alternative approaches that can dodge these limitations are being tried and adopted. Present work is an attempt to highlight various advancements that are being investigated at different phases of drug development for management of HD and related pathogenesis. Authors have made significant efforts to discuss various molecular and cellular pathways as a potential drug target for the management of HD and related problems.

References

  1. 1.
    Jamwal S, Kumar P. Antidepressants for neuroprotection in Huntington’s disease: a review. Eur J Pharmacol. 2016;769:33–42.CrossRefGoogle Scholar
  2. 2.
    Mestre TA, Sampaio C. Huntington disease: linking pathogenesis to the development of experimental therapeutics. Curr Neurol Neurosci Rep. 2017;17:18.CrossRefGoogle Scholar
  3. 3.
    Tanaka M, Ishizuka K, Nekooki-Machida Y, Endo R, Takashima N, Sasaki H, Komi Y, Gathercole A, Huston E, Ishii K, Hui KK. Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease. J Clin Invest. 2017;127(4):1438–50.  https://doi.org/10.1172/JCI85594.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutic targets in Huntington’s disease. Physiol Rev. 2010;90:905–81.CrossRefGoogle Scholar
  5. 5.
    Pla P, Orvoen S, Saudou F, David DJ, Humbert S. Mood disorders in Huntington disease: from behaviour to cellular and molecular mechanism. Front Behav Neurosci. 2014;8:135.CrossRefGoogle Scholar
  6. 6.
    Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009;5:311–22.CrossRefGoogle Scholar
  7. 7.
    Velusamy T, Panneerselvam AS, Purushottam M, Anusuyadevi M, Pal PK, Jain S, Essa MM, Guillemin GJ, Kandasamy M. Protective effect of antioxidants on neuronal dysfunction and plasticity in Huntington’s disease. Oxidative Med Cell Longev. 2017;2017:3279061.CrossRefGoogle Scholar
  8. 8.
    Kumar P, Kalonia H, Kumar A. Huntington’s disease: pathogenesis to animal models. Pharmacol Rep. 2010;62:1–14.CrossRefGoogle Scholar
  9. 9.
    Kumar P, Naidu PS, Padi SSV, Kumar A. Huntington’s disease: a review. Indian J Pharm Educ Res. 2007;41:287–94.Google Scholar
  10. 10.
    Zeron MM, Fernandes HB, Krebs C, Shehadeh J, Wellington CL, Leavitt BR, Baimbridge KG, Hayden MR, Raymond LA. Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington’s disease. Mol Cell Neurosci. 2004;25:469–79.CrossRefGoogle Scholar
  11. 11.
    Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron. 2002;33:849–60.CrossRefGoogle Scholar
  12. 12.
    Kalonia H, Kumar P, Kumar A. Attenuation of pro-inflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington’s like alteration in rats. Brain Res. 2011a;1372:115–26.CrossRefGoogle Scholar
  13. 13.
    Kalonia H, Kumar P, Kumar A. Licofelone attenuates quinolinic acid induced Huntington’s like symptoms: possible behavioural, biochemical and cellular alterations. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011b;35:607–15.CrossRefGoogle Scholar
  14. 14.
    Sanchez I, Mahlke C, Yuan J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature. 2003;421:373–9.CrossRefGoogle Scholar
  15. 15.
    Augood SJ, Faull RL, Emson PC. Dopamine D1 and D2 receptor gene expression in the striatum in Huntington’s disease. Ann Neurol. 1997;42:215–21.CrossRefGoogle Scholar
  16. 16.
    Augood SJ, Faull RL, Love DR, Emson PC. Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington’s disease: a detailed cellular in situ hybridization study. Neuroscience. 1996;72:1023–36.CrossRefGoogle Scholar
  17. 17.
    Fernandes HB, Baimbridge KG, Church J, Hayden MR, Raymond LA. Mitochondrial sensitivity and altered calcium handling underlie enhanced NMDA-induced apoptosis in YAC128 model of Huntington’s disease. J Neurosci. 2007;27:13614–23.CrossRefGoogle Scholar
  18. 18.
    Duan W, Peng Q, Masuda N, Ford E, Tryggestad E, Ladenheim B. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington’s disease. Neurobiol Dis. 2008;30:312–22.CrossRefGoogle Scholar
  19. 19.
    Hersch S, Fink K, Vonsattel JP, Friedlander RM. Minocycline is protective in a mouse model of Huntington’s disease. Ann Neurol. 2003;54:841–3.CrossRefGoogle Scholar
  20. 20.
    Wang CE, Zhou H, McGuire JR, Cerullo V, Lee B, Li SH, Li XJ. Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol. 2008;181:803–16.CrossRefGoogle Scholar
  21. 21.
    Francelle L, Lotz C, Outeiro T, Brouillet E, Merienne K. Contribution of neuroepigenetics to Huntington’s disease. Front Hum Neurosci. 2017;11:17.CrossRefGoogle Scholar
  22. 22.
    Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Neri C. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet. 2005;37:349–50.CrossRefGoogle Scholar
  23. 23.
    Viswanathan M, Kim SK, Berdichevsky A, Guarente L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell. 2005;9:605–15.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Puneet Kumar
    • 1
  • Sumit Jamwal
    • 2
    • 3
  • Anil Kumar
    • 4
  1. 1.Department of PharmacyMaharaja Ranjit Singh Punjab Technical UniversityBathindaIndia
  2. 2.Department of PharmacologyISF College of PharmacyMogaIndia
  3. 3.School of Pharmacy and Emerging SciencesBaddi University of Emerging Sciences and TechnologiesBaddiIndia
  4. 4.University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies (UGC-CAS), Panjab UniversityChandigarhIndia

Personalised recommendations