Excitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease

Sanchez, A.; Mejía-Toiber, Jana; Massieu, Lourdes

doi:10.1016/j.arcmed.2007.11.011

Cited by 188 publications

(105 citation statements)

References 108 publications

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“…QA is an excitotoxic agent, which has been implicated in the pathogenesis of several neuroinflammatory and neurodegenerative diseases including HD [24,25] . It has been now well elucidated that increased expression level of COX-2 occurs mainly through activation of NMDA receptors [26] , although few studies have reported the involvement of LOX pathway in these neurodegenerative disorders [27,28] .…”

Section: Discussionmentioning

confidence: 99%

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Kalonia

Kumar

et al. 2009

Neurosci. Bull.

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Objective The neuroprotective roles of cyclooxygenase (COX) and lipooxygenase (LOX) inhibitors have been well documented. Quinolinic acid (QA) is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington's disease (HD), by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid (a specific inhibitor for LOX), rofecoxib (a specific inhibitor for COX-2), and their combination in ameliorating QAinduced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration (300 nmol) not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status (decreased glutathione and increased oxidized glutathione level) in striatum, as compared to the sham group.Moreover, chronic treatment with caffeic acid (5 mg/kg and 10 mg/kg, respectively, p.o.) or rofecoxib (10 mg/kg, p.o.) could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib (10 mg/kg) and caffeic acid (5 mg/kg) could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.

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Section: Discussionmentioning

confidence: 99%

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Kalonia

Kumar

et al. 2009

Neurosci. Bull.

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“…Nevertheless, other mechanisms including glutamatemediated excitotoxicity, acidotoxicity, and inflammation are thought to participate in the process of neuronal injury 13 . The role of glutamate excitotoxicity has been demonstrated in focal ischaemic model 14 and several neurodegenerative diseases [15][16][17] . However, further detailed study about glutamate excitotoxicity involvement in chronic cerebral hypoperfusion has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

Koomhin¹,

Tilokskulchai²,

Tapechum

2012

ScienceAsia

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Cerebral hypoperfusion is associated with cognitive decline in ageing, mild cognitive impairment, vascular type dementia, and Alzheimer's disease. The mechanisms leading to such neurological impairments are still uncertain. Although several mechanisms have been proposed as contributing factors leading to neuronal injury, glutamate excitotoxicity seems to be the relevant one. Recently, it was found that β-lactam antibiotics such as ceftriaxone show a neuroprotective effect by upregulation of glutamate transporter and reduction of glutamate excitotoxicity. To study the contribution of glutamate excitotoxicity and the effects of ceftriaxone on spatial learning and memory in chronic cerebral hypoperfusion, we conducted experiments in rats subjected to permanent bilateral common carotid artery occlusion. Ceftriaxone (200 mg/kg) was injected daily in rats for 5 days after the onset of the arterial ligation. A Morris water maze was used to assess learning and memory two months after arterial ligation. Hippocampal histology and glutamate transporter 1 (GLT-1) expression were also studied. Results showed that ceftriaxone improved learning and memory performance. Consistently, the histological study showed an increase hippocampal CA1 and CA3 neuronal numbers in the ceftriaxone-treated group compared with the vehicle-treated group. Although not statistically significant, the GLT-1 protein level in the hippocampus was 86% higher than the sham group. We conclude that ceftriaxone treatment can attenuate neuronal injury and improve spatial learning and memory after chronic cerebral hypoperfusion and that glutamate excitotoxicity may play an important role in the pathophysiology of chronic cerebral hypoperfusion.

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“…61,62 Eksitotoksisitenin Huntington hastalığının yanı sıra iskemik retinopati, inme, MSS travması, epilepsi, Parkinson hastalığı, amiyotrofik lateral skleroz ve Alzheimer hastalığı gibi çeşitli nöronal hastalıklarda rol oynadığı kanıtlanmıştır. [63][64][65][66][67][68][69][70] Sinaptik NMDAR aktivitesi ile nöronlar için koruyucu rol oynayacak gen ifadeleri sağlanırken, ekstrasinaptik aktiviteler hücre ölümünü tetikler. 69 Sinaptik ve ekstrasinaptik NMDAR aktiviteleri arasındaki dengenin bozulmasının nöronlarda fonksiyon kaybına yol açtığı belirlenmiştir.…”

Section: N-meti̇l-d-aspartat Reseptörleri̇unclassified

“…55,56,68 Eksitotoksisite, uyarıcı amino asit reseptörlerinin aktivasyonu nedeniyle nöron ölümü olarak tanımlanır. NMDAR'nin uyarıcı bir amino asit olan glutamat ile uzun süreli aktivasyonu ve bunun sonucu olarak kaspazların aktiflenmesi, NFκB'nin serbestlenerek çekirdeğe geçişi ve c-myc, p53 gibi genlerin transkripsiyonlarının artışı söz konusudur.…”

Section: Sonuçunclassified

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

Tüfekçi¹,

Tunalı²

2012

Turkiye Klinikleri J Med Sci

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201Huntington Hastalığında Toksisite Mekanizmaları ve NMDAR-Aracılı Eksitotoksisitede Poliaminlerin Rolü Ö ÖZ ZE ET T Huntington hastalığı, istemsiz koreik hareketler, bilişsel kayıplar ve psikolojik bozukluklarla karakterize edilen, otozomal dominant geçişli, geç başlangıçlı ve ölümcül bir hastalıktır. Hastalığa sebep olan mutasyon, IT-15 geninin birinci eksonunda tekrar eden CAG bazlarının sayılarındaki artıştır. Mutant genin ifadesi, striyatal gamma aminobütirik asit ileten (GABA-erjik) orta boy dikensi nöronların seçimli ölümüne neden olur. Mutant huntingtin (htt) proteininin konformasyonu, protein yıkımı ve übikütin-proteozom sistemi (UPS), gen yazılımı düzenlemelerin-deki değişimler ve eksitotoksisite, nörodejenerasyonun moleküler mekanizmaları arasındadır. Uyarıcı kimyasalların aşırı miktarı hücreleri sürekli uyararak hassas hücrelerin eksitotoksik ölüm-lerine sebep olurlar. Glutamat da bazal gangliyadan salınan uyarıcı nörotransmiterlerden biridir. Huntington hastalığında striyatal nöronların kaybedilmesi glutamat reseptörü aracılı eksitotoksisitenin patogenezde etkili olabileceğine işaret eder. İyonotrofik glutamat reseptörleri (iGluR) arasın-dan biri olan N-metil-D-Aspartat reseptörleri (NMDAR)'nin uyarılması ve bunu takiben nükleer faktör kappa B (NF ± B) yazılım faktörünün aktivasyonu nöronal ölüm ile sonuçlanır. NMDAR, glutamat bağlanma bölgelerine ek olarak poliamin bağlanma bölgeleri de içerir. Poliaminlerin mutant htt proteininin, NMDAR ve NF ± B yazılım faktörü ile ayrı ayrı ilişki içerisinde olması, bu proteinin, Huntington hastalığında meydana gelen nörodejenerasyonda merkezi bir rol oynayabileceğini düşündürmektedir. Bu nedenle, Huntington hastalığında poliamin metabolizmasının detaylı araştı-rılması ve anlaşılması hastalığın tedavisinde yeni yaklaşımlar üretilmesini sağlayacaktır.A An na ah ht ta ar r K Ke el li im me el le er r: : Huntington hastalığı; NR2A NMDA reseptörü; reseptörler, glutamat; poliaminler A AB BS ST TR RA AC CT T Huntington's Disease is an autosomal dominant, late onset and fatal disorder characterized by involuntary choreic movements, cognitive dysfunction and psychological disturbances. The causative mutation is the expansion of the CAG repeats in the first exon of the IT-15 gene. Mutant gene expression causes selective death of striatal gamma aminobutyric acid releasing (GABA-ergic) medium size spiny neurons. Changes in the conformation of the mutant huntingtin (htt) protein, proteolysis and ubiquitin-proteasome system (UPS), transcriptional disregulation and excitotoxicity are among the molecular mechanisms of neurodegeneration. Excess amounts of excitatory chemicals continuously stimulate the cells and cause excitotoxic death of vulnerable cells. Glutamate is one of the excitatory neurotransmitters released from basal ganglia. The striatal neuron loss in Huntington's Disease points out that glutamate receptor mediated excitotoxicity may play a role in the pathogenesis. Excitation of N-methyl-D-Aspartate receptors (NMDARs), which belong to ionotrophic glutamate recept...

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Excitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease

Cited by 188 publications

References 108 publications

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

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