Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease

Abstract

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neuropathological changes similar to those observed in Huntington's disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial modulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mitochondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission electron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA + ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD.

Spatiotemporal expression of osteopontin in the striatum of rats subjected to the mitochondrial toxin 3-nitropropionic acid correlates with microcalcification

“…Nonetheless, mitochondrial toxicity is the key to 3-NP neurotoxicity, and mitochondrial dysfunction caused by 3-NP may impair calcium ion sequestration and lead to calcium overload3536. In addition, 3-NP irreversibly increases intracellular calcium63, and injured neurons initially show mitochondrial swelling with disorganised cristae, indicating that early events in 3-NP-induced neurotoxicity involve mitochondrial damage64656667. In this regard, intramitochondrial expression of OPN in the 3-NP model indicates that OPN may act as a potent regulator of mitochondrial calcium homeostasis and/or intracellular calcification process34.…”

Simultaneous lipidomic and transcriptomic profiling in mouse brain punches of acute epileptic seizure model compared to controls

“…Parkinson's disease (14,15), Huntington's disease (16,17), and schizophrenia (18,19). Epilepsy, one of the most common neurological disorders worldwide, was also correlated with pathophysiological changes in PL metabolism (20)(21)(22) and eCB signaling (23,24).…”

Experimental Models in Neurodegenerative Diseases

“…Bu modeller, HH'ye özgü bilişsel ve davranışsal belirtileri hızlı bir şekilde ortaya çıkartırlar (47). Bu modellerden biri olan R6/2 fare modeli, semptomların en hızlı gelişmesini sağlayan ve beyinde huntingtin kalıntılarının en yaygın oluştuğu modeldir (48).…”

“…mHTT'nin etkilerini seçici olarak taklit etmeyi amaçlarlar. Bu modellerde lezyon oluşturmak için kullanılan yöntemler; glutamat reseptör agonistlerinin sitriatal alana doğrudan enjeksiyonu, bazı nörotoksinler ve mitokondrial toksinlerin periferik uygulamaları şeklindedir (47,48).…”

“…Glutamat beyindeki ana uyarıcı nörotransmitterdir ve sinyal iletisindeki bozukluklar HH dahil birçok nörolojik bozuklukla ilişkilidir. Nörotoksin enjeksiyonu ile oluşturulan ilk model olan kainik asit/ibutenik asit modeli, HH'den etkilenen ve etkilenmeyen nöronları ayırabilirken, mitokondrial toksin uygulamaları bilateral akut sitrial hasar oluşturmaları yönünden önemlidir (47,48).…”