Neuroprotective Effect of Lutein Against 3-Nitropropionic Acid–Induced Huntington's Disease–Like Symptoms: Possible Behavioral, Biochemical, and Cellular Alterations

Abstract

3-Nitropropionic acid (3-NP) induces cellular energy deficit and oxidative stress-related neurotoxicity via an irreversible inhibition of mitochondrial complex II enzyme, succinate dehydrogenase. Huntington's disease (HD) is a neurological disorder characterized by cognitive and motor dysfunctions. Lutein is a well-known antioxidant used in the management of oxidative stress related diseases. Clinical trials have supported the beneficial effect of lutein in Alzheimer's disease. The present study was designed to explore possible neuroprotective effects of lutein on 3-NP-induced mitochondrial dysfunction and oxidative stress. Systemic administration of 3-NP (25 mg/kg intraperitoneally [i.p.] for 4 consecutive days) caused loss of body weight and neurobehavioral deficits by hind-limb impairment (Narrow Beam test), motor coordination (locomotor activity) and memory dysfunction (Morris water maze and Elevated Plus maze performance). Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration, reduced gutathione levels, and acetyl cholinesterase levels and depleted catalase activities in rat brain. The activities of mitochondrial complexes (I, II, IV, and MTT assay) were found to be significantly lowered in brain mitochondria. Daily lutein (50 or 100 mg/kg orally [p.o.]) administration for 14 days significantly improved body weight, neurobehavioral alterations and attenuated oxidative stress and improved mitochondrial enzymes complex activities of rat brain. Histopathological examination further affirmed the neuroprotective effect of lutein on 3-NP induced pathological lesions. The present study indicates that lutein is a promising candidate for the management of HD and related conditions.

Mitochondrial modulators in experimental Huntington’s disease: reversal of mitochondrial dysfunctions and cognitive deficits

“…In addition, MTT reduction (a marker of mitochondrial functioning) was markedly reduced in the striatum of 3-NPetreated animals. Mitochondrial complex-II has been reported to, at least partly, involved in MTT reduction by intact astrocytes and neurons (Binawade and Jagtap, 2013), thus confirming inhibition of SDH by 3-NP. Such an overall metabolic defect observed in the administration of 3-NP contributed to impaired ATP energy production via F 1 F 0 synthase, which is in accordance with earlier findings (Hollmann et al, 2008).…”

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…In the experimental animal model, it caused mitochondrial dysfunction, oxidative stress, biochemical imbalance, neuroinflammation, apoptosis, and autophagy, leading to neuronal cell death (Binawade and Jagtap, 2013; Solesio et al, 2013; Shetty et al, 2015; Jamwal and Kumar, 2016; Thangarajan et al, 2016). 3-NP was shown to produce neurotoxicity via the modulation of glutamate receptors.…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…Further, it is also having a potential protective effect against mitochondrial metabolic impairment and oxidative stress induced by 3-NP PD and HD [153,154] (continued on next page) are numerous other emerging therapeutic strategies that have been identified currently to target such alterations. For instance, a neuroprotective effect of Lithium has been reported via modulation of mitochondrial dysfunction, which is likely achieved by impeding GSK-3 and inositol-145 triphosphate (IP 3 ) in AD [183].…”