Huntington’s disease: Pathophysiology and therapeutic intervention

Payal B  Kshirsagar; Hemant S  Kanhere; Pallavi C  Bansinge; Sawan K; Vrushali S  Khandare; Ranjita K  Das

doi:10.30574/gscbps.2021.15.2.0140

Authors

Payal B Kshirsagar Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.
Hemant S Kanhere Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.
Pallavi C Bansinge Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.
Sawan K Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.
Vrushali S Khandare Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.
Ranjita K Das Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002 (M.S.), India.

DOI:

https://doi.org/10.30574/gscbps.2021.15.2.0140

Keywords:

Huntington's disease, Neurotransmission, Etiology, Pathophysiology, Treatment

Abstract

Huntington's disease [HD] is a progressive neurodegenerative condition characterized by movement disorder, cognitive impairment, and behavioral symptoms. It is inherited as an autosomal-dominant trait and normally manifests in mid-adulthood. HD is common in India and parts of Central Asia, with a prevalence rate of 4–8 per 100 000 in most European populations. Juvenile onset affects around 5–10% of cases, with signs appearing before the age of 20. Patients may show more parkinsonian symptoms such as bradykinesia, dystonia, tremors and a cognitive deficit in place of chorea. There is no therapy that can completely stop the condition from progressing. There are medications that can help to regulate chorea, dystonia, mental, and psychiatric disturbances. The study covers the disease's pathophysiology, as well as plants and phytochemicals that have been shown to be beneficial.

Metrics

Metrics Loading ...

References

Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, Rosser A. Targeting huntingtin expression in patients with Huntington’s disease. New England Journal of Medicine. 2019;380(24):2307-16.

Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron. 2019;101(5):801-19.

Zheng Z, Diamond MI. Huntington disease and the huntingtin protein. Progress in molecular biology and translational science. 2012;107:189-214.

Frank S, Jankovic J. Advances in the pharmacological management of Huntington’s disease. Drugs. 2010;70(5):561-71.

Coppen EM, Roos RA. Current pharmacological approaches to reduce chorea in Huntington’s disease. Drugs. 2017;77(1):29-46.

Ribaï P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, Legout A, Dodé C, Brice A, Dürr A. Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients. Archives of neurology. 2007;64(6):813-9.

Jankovic J, Roos RA. Chorea associated with Huntington's disease: to treat or not to treat?. Movement Disorders. 2014;29(11):1414-8.

Reiner A, Albin RL, Anderson KD, D'Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proceedings of the National Academy of Sciences. 1988;85(15):5733-7.

Bates G, Tabrizi S, Jones L. eds. Huntington's disease. Oxford Monographs on Medical G. 2014.

Frank S. Treatment of Huntington’s disease. Neurotherapeutics. 2014 Jan;11(1):153-60.

Andre´ VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington’s disease: a balancing act. CNS NeurosciTher. 2010;16:163–78.

Schwab LC, Garas SN, Drouin-Ouellet J, Mason SL, Stott SR, Barker RA. Dopamine and Huntington’s disease. Expert Rev Neurother. 2015;15:445–58.

Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217.

Pagano G, Niccolini F, Politis M. Current status of PET imaging in Huntington’s disease. Eur J Nucl Med Mol Imaging. 2016;43:1171–82.

Pavese N, Andrews TC, Brooks DJ, Ho AK, Rosser AE, Barker RA, et al. Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: a PET study. Brain. 2003;126:1127–35.

Ginovart N, Lundin A, Farde L, Halldin C, Ba¨ckman L, Swahn CG, et al. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington’s disease. Brain. 1997;120:503–14.

Andrews TC, Weeks RA, Turjanski N, Gunn RN, Watkins LH, Sahakian B, et al. Huntington’s disease progression. PET and clinical observations. Brain. 1999;122:2353–63.

Carroll JB, Bates GP, Steffan J, Saft C, Tabrizi SJ. Treating the whole body in Huntington’s disease. Lancet Neurol. 2015;14:1135–42.

The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. TheHuntington’s Disease Collaborative Research Group. 1993;72: 971-983.

Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington's disease. Nature Reviews Neuroscience. 2005;6(12):919-30.

Walker FO. Huntington's disease. The Lancet. 2007;369(9557):218-28.

Imarisio S, Carmichael J, Korolchuk V, Chen CW, Saiki S, Rose C, Krishna G, Davies JE, Ttofi E, Underwood BR, Rubinsztein DC. Huntington's disease: from pathology and genetics to potential therapies. Biochemical Journal. 2008;412(2):191-209.

Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. an International Huntington's Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clinical genetics. 2004 Apr;65(4):267-77.

Wheeler VC, Persichetti F, McNeil SM, Mysore JS, Mysore SS, MacDonald ME, Myers RH, Gusella JF, Wexler NS, US–Venezuela Collaborative Research Group. Factors associated with HD CAG repeat instability in Huntington disease. Journal of medical genetics. 2007;44(11):695-701.

Reiner A, Dragatsis I, Dietrich P. Genetics and neuropathology of Huntington's disease. International review of neurobiology. 2011;98:325-72.

Illarioshkin SN, Klyushnikov SA, Vigont VA, Seliverstov YA, Kaznacheyeva EV. Molecular pathogenesis in Huntington’s disease. Biochemistry (Moscow). 2018;83(9):1030-9.

Myers RH. Huntington’s disease genetics. NeuroRx. 2004 Apr;1(2):255-62.

Ajitkumar A, De Jesus O. Huntington Disease. StatPearls [Internet]. 2020 Jul 6.

Bates G. Huntingtin aggregation and toxicity in Huntington’s disease. Lancet. 2003; 361 (9369): 1642-4.

Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004; 431(7010): 805-10.

Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nature Reviews Neurology. 2009;5(6):311.

Pla P, Orvoen S, Saudou F, David DJ, Humbert S. Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms. Frontiers in behavioral neuroscience. 2014;8:135.

Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature genetics. 1995;11(2):155-63.

Borrell-Pages M, Zala D, Humbert S, Saudou F. Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies. Cellular and Molecular Life Sciences CMLS. 2006;63(22):2642-60.

Gill JM, Rego AC. Mechanism of neurodegeneration in Huntington’s dinase. Eur JNeurosci. 2008; 27(11): 2803-2820.

Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998 Oct;95(1):55-66.

Chen CM. Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington's disease. Chang Gung Med J. 2011;34(2):135-52.

Jamwal S, Kumar P. Antidepressants for neuroprotection in Huntington's disease: A review. European journal of pharmacology. 2015;769:33-42.

Labbadia J, Morimoto RI. Huntington's disease: underlying molecular mechanisms and emerging concepts. Trends in biochemical sciences. 2013;38(8):378-85.

Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s disease: mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harbor perspectives in medicine. 2017;7(7):a024240.

Kumar A, Vaish M, Ratan RR. Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis. Drug discovery today. 2014 Jul 1;19(7): 956-62.

Kumar P, Padi SS, Naidu PS, Kumar A. Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes: possible neuroprotective mechanisms. Behavioural pharmacology. 2006;17(5-6):485-92.

Kumar P, Kalonia H, Kumar A. Sesamol attenuate 3-nitropropionic acid-induced Huntington-like behavioral, biochemical, and cellular alterations in rats. Journal of Asian natural products research. 2009;11(5):439-50.

Chen CM. Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington's disease. Chang Gung Med J. 2011 Mar 1;34(2):135-52.

Quintanilla RA, Johnson GV. Role of mitochondrial dysfunction in the pathogenesis of Huntington's disease. Brain research bulletin. 2009;80(4-5):242-7.

DiFiglia M. Excitotoxic injury of the neostriatum: a model for Huntington's disease. Trends in neurosciences. 1990;13(7):286-9.

Kalonia H, Kumar P, Kumar A. Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats. Brain research. 2011;1372:115-26.

Kalonia H, Kumar P, Kumar A. Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2011;35(2):607-15.

Kumar P, Kalonia H, Kumar A. Expression of Concern: Role of LOX/COX pathways in 3‐nitropropionic acid‐induced Huntington's Disease‐like symptoms in rats: protective effect of licofelone. British journal of pharmacology. 2011;164(2b):644-54.

Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. New England Journal of Medicine. 2003;348(14):1365-75.

Leegwater-Kim J, Cha JH. The paradigm of Huntington's disease: therapeutic opportunities in neurodegeneration. NeuroRx. 2004;1(1):128-38.

Li SH, Lam S, Cheng AL, Li XJ. Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Human molecular genetics. 2000;9(19):2859-67.

Myers RH. Huntington’s disease genetics. NeuroRx. 2004;1(2):255-62.

Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, Kennard C, Hicks SL, Fox NC, Scahill RI, Borowsky B. Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. The Lancet Neurology. 2009;8(9):791-801.

Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard C. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. The Lancet Neurology. 2011;10(1):31-42.

Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks SL, Kennard C. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. The Lancet Neurology. 2012;11(1):42-53.

Tabrizi SJ, Scahill RI, Owen G, Durr A, Leavitt BR, Roos RA, Borowsky B, Landwehrmeyer B, Frost C, Johnson H, Craufurd D. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. The Lancet Neurology. 2013;12(7):637-49.

Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, Guttman M, Johnson S, MacDonald M, Beglinger LJ, Duff K. Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. Journal of Neurology, Neurosurgery & Psychiatry. 2008;79(8):874-80.

Harrington DL, Smith MM, Zhang Y, Carlozzi NE, Paulsen JS. PREDICT-HD Investigators of the Huntington Study Group. Cognitive domains that predict time to diagnosis in prodromal Huntington disease. Journal of Neurology, Neurosurgery & Psychiatry. 2012;83(6):612-9.

Biglan KM, Zhang Y, Long J, Geschwind M, Kang G, Killoran A, Lu W, McCusker E, Mills JA, Raymond LA, Testa C. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Frontiers in aging neuroscience. 2013;5:12.

Aylward EH, Nopoulos PC, Ross CA, Langbehn DR, Pierson RK, Mills JA, Johnson HJ, Magnotta VA, Juhl AR, Paulsen JS. PREDICT-HD Investigators. Longitudinal change in regional brain volumes in prodromal Huntington disease. Journal of Neurology, Neurosurgery & Psychiatry. 2011;82(4):405-10.

Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, Scahill RI, Leavitt BR, Stout JC, Paulsen JS, Reilmann R. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nature Reviews Neurology. 2014;10(4):204.

Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. The Journal of clinical investigation. 2015;125(5):1979-86.

Rodrigues FB, Byrne L, McColgan P, Robertson N, Tabrizi SJ, Leavitt BR, Zetterberg H, Wild EJ. Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease. Journal of neurochemistry. 2016 ;139(1):22-5.

Byrne LM, Rodrigues FB, Blennow K, Durr A, Leavitt BR, Roos RA, Scahill RI, Tabrizi SJ, Zetterberg H, Langbehn D, Wild EJ. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. The Lancet Neurology. 2017;16(8):601-9.

Ghosh R, Tabrizi SJ. Huntington disease. Handbook of clinical neurology. 2018;147:255-78.

Gohil KJ, Patel JA. A review on Bacopamonniera: current research and future prospects. International Journal of Green Pharmacy (IJGP). 2010;4(1).

Russo A, Borrelli F. Bacopamonniera, a reputed nootropic plant: an overview. Phytomedicine. 2005;12(4):305-17.

Choudhary S, Kumar P, Malik J. Plants and phytochemicals for Huntington's disease.Pharmacognosy Reviews. 2013;7(14):81.

Ratheesh G, Tian L, Venugopal JR., Ezhilarasu H, Sadiq A, FanTP, Ramakrishna S. Role of medicinal plants in neurodegenerative diseases. Biomanufacturing Reviews.2017;2(1): 1-16.

Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withaniasomnifera. Indian journal of experimental biology. 1997;35:236-9.

Davis L, Kuttan G. Effect of Withaniasomnifera on cell mediated immune responses in mice. Journal of experimental & clinical cancer research: CR. 2002;21(4):585-90.

Kumar P, Kumar A. Possible neuroprotective effect of Withaniasomnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington's disease. Journal of medicinal food. 2009;12(3):591-600.

Kumar P, Kumar A. Effects of root extract of Withaniasomniferain 3‑Nitropropionic acid‑induced cognitive dysfunction andoxidative damage in rats. Int J Health Res. 2008;1:139‑49.

Nakanishi K. Terpene trilactones from Gingko biloba: From ancient times to 21st century. Bioorg Med Chem. 2005;13:4987‑5000.

McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of Ginkgo bilobain clinical and preclinical applications. AlternTher Health Med 2001;7:70‑86, 88‑90.

Ramassamy C, Longpre F, Christen Y. Ginkgo bilobaextract (EGb 761) in Alzheimer’s disease: Is there any evidence? Curr Alzheimer Res. 2007;4:253‑62.

Handa SS. Rasaayana Drugs Part‑I. Pharm Times. 1993;25:9‑15.

Shinomol GK, Muralidhara. Prophylactic neuroprotectiveproperty of Centellaasiatica against 3‑nitropropionic acid induced oxidative stress and mitochondrial dysfunctions in brain regions of prepubertal mice. Neurotoxicology. 2008;29:948‑57.

Nah SY, Kim DH, Rhim H. Ginsenosides: Are any of them candidates for drugs acting on central nervous system. CNS Drug Rev 2007;13:381‑404.

Lu JM, Yao Q, Chen C. Ginseng compounds: An update on their molecular mechanisms and medical applications. CurrVascPharmacol. 2009;7:293‑302.

Wu J, Jeong HK, Bulin SE, Kwon SW, Park JH, Bezprozvanny I. Ginsenosides protect striatal neurons in cellular model of Huntington’s disease. J Neurosci Res. 2009;87:1904‑12.

Ren W, Qiao Z, Wang H, Zhu L, Zhang L. Flavonoids: Promising anticancer agents. Med Res Rev. 2003;23:519‑34.139.

Narayana KR, Reddy MS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemicaleffects and therapeutic potential. Indian J Pharmacol. 2001;33:2‑16.

Schroeter H, Boyd C, Spencer JP, Williams RJ, CadenasE,Rice‑Evans C. MAPK signaling in neurodegeneration: Influences of flavonoids and of nitric oxide. Neurobiol Aging. 2001;23:861‑80.

Lopez‑Lopez G, Moreno L, Cogolludo A, Galisteo M, Ibarra M, Duarte J, et al. Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle. MolPharmacol. 2004;65:851‑9.

Kumar P, Padi SS, Naidu PS, Kumar A. Cyclooxygenase inhibition attenuates 3‑nitropropionic acid‑induced neurotoxicity in rats: Possible antioxidant mechanisms. FundamClinPharmacol. 2007;21:297‑306.

Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free RadicBiol Med. 2001;30:433‑46.

Kumar A, Singh SK, Kumar V, Kumar D, Agarwal S, Rana MK. Huntington's disease: an update of therapeutic strategies. Gene. 2015;556(2):91-7.

Wang H, Chen X, Li Y, Tang TS, Bezprozvanny I. Tetrabenazine is neuroprotective in Huntington's disease mice. Molecular neurodegeneration. 2010;5(1):1-2.

Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, Kinel S, Leavitt B, Oakes D, O’Neill C, Vaughan C. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. Jama. 2016;316(1):40-50.

Reilmann R. Deutetrabenazine—Not a revolution but welcome evolution for treating chorea in huntington disease. JAMA neurology. 2016;73(12):1404-6.

Potkin KT, Potkin SG. New directions in therapeutics for Huntington disease. Future neurology. 2018;13(2):101-21.

Novak MJ, Tabrizi SJ. Huntington’s disease. 2010;340.

Low PA, Allsop JL, Halmayi G. The rigid form (Westphal variant) of Huntington's disease treated with levodopa. Med J Aust. 1974;1:393-4.

Bonelli RM, Niederwieser G, Diez J, Gruber A, Költringer P. Pramipexole ameliorates neurologic and psychiatric symptoms in a Westphal variant of Huntington's disease. Clinical neuropharmacology. 2002;25(1):58-60.

Panchal K, Tiwari AK. Mitochondrial dynamics, a key executioner in neurodegenerative diseases. Mitochondrion. 2019;47:151-73.

Kanhere HS, Rahangdale YU, Bodele AS, Wadhwani DI, Ghoshewar AR, Karande SP. Neurological disorders associated with impaired gut microbiota. GSC Biological and Pharmaceutical Sciences. 2021;15(2):029-39.

Wasser CI, Mercieca EC, Kong G, Hannan AJ, McKeown SJ, Glikmann-Johnston Y, Stout JC. Gut dysbiosis in Huntington’s disease: associations among gut microbiota, cognitive performance and clinical outcomes. Brain communications. 2020;2(2):fcaa110.