5,6,7 trihydroxy flavone armoured neurodegeneration caused by Quinolinic acid induced huntington’s like disease in rat striatum - reinstating the level of brain neurotrophins with special reference to cognitive-socio behaviour, biochemical and histopathological aspects

Highlights

• Baicalein attenuates motor-cognitive abnormalities of QA induced striatal lesion.

• Brain neurotrophins levels were augmented after baicalein administration.

• QA reverses GABAergic inhibition studied via TH immunohistochemical analysis.

• Baicalein restrained the antioxidant disturbance due QA lesion in striatal region.

Abstract

Huntington Disease (HD), a predominant Neurodegenerative Disorder which might be induced by endogenous neurotoxin called Quinolinic Acid (QA), an N-methyl-D aspartate receptor (NMDAR) agonist, the bilaterally intrastriatal administration (200 nm/2 μL of saline) offers rise to the toxic events like neuronal death, neuroinflammation by inflicting excitotoxicity and oxidative stress in the striatum of male Wistar rats by exhibiting the behavioural changes which was accessed by rotarod, open field analysis. In this study, the neuropharmacological effect of Baicalein (BC) against QA induced HD was evaluated. Baicalein (BC), scientifically 5,6,7 trihydroxy flavone present naturally in the edible plants like Scutellaria baicalensis and Oroxylum indicum possess a better neuroprotective effect in the dosage of 10 mg/kg and 30 mg/kg intraperitoneally in the striatum of HD induced rats. This study proved that BC is efficient to revive the level of enzymatic & non-enzymatic antioxidants and mitochondrial complexes by decreasing the number of inflammatory mediators such as MDA, protein carbonyls and Nitric Oxide at the significance of P < 0.01 and restores the amount of BDNF and GDNF thereby preventing the neurophysiological changes which were analysed by haematoxylin & eosin staining. Thus finally, the protective effect of Baicalein displays the up-gradation of psychological and behavioural changes induced by QA.

Introduction

Neurodegenerative diseases like Huntington Disease (HD), are autosomal disorders mainly due to the death of the brain cells which can be characterized by the hyperkinetic movement disorders such as motor coordination impairment, depressive and cognitive symptoms (Brouillet, 2014). The pathogenetic feature of HD is said to be ≥ 36 CAG trinucleotide repeat expansion located at the exon 1 of chromosome 4 in HD gene (McDonald et al., 1993). As the year’s signs of progress, HD is anticipated to be a world-wide health problem (Carmona-Ramírez et al., 2013). These forms of neurodegenerative diseases are triggered by the initiation of harmful cascades (Nakamura and Animoff, 2007) via disruptive Ca²⁺ homeostasis, reactive oxygen and nitrogen-oxygen species conscription which led to cell death by oxidative stress (Santamaria and Jimenez, 2005).

Intrastriatal administration of QA toxicity involves chiefly within the activation of N-methyl-d-aspartate (NMDA) receptor which initiates several pathological hallmarks similar to the HD pathogenesis, overload Ca²⁺ concentration in the cytosol, reduction of γ-aminobutyric acid (GABA), depletion of ATP level thereby it leads to oxidative cell damage (Foster et al., 1983) and abnormalities in the endogenous antioxidant system (Leipnitz et al., 2005). Several studies reveal that neuroinflammation and increased ROS generation result into mitochondrial energy deficient (Uttara et al., 2009). Under other diseased conditions such as Alzheimer’s disease, acquired immunodeficiency syndrome (AIDS)-dementia complex, an increasing level of QA is found (Sardar et al., 1995; Guillemin et al., 2005), and by changes in the kynurenine pathway (Maddison and Giordini, 2015).

Baicalein (BC) is an 5,6,7-trihydroxyflavone found in the traditional Chinese herb Scutellaria baicalensis Georgi, Oroxylum indicum (Indian trumpet flower) and Thymus vulgaris (Matsumoto, 2008) and has been shown to have anti-inflammatory properties through antioxidant and free radical scavenging activity (Hamada et al., 1993) as well as neuroprotective properties in the AD cellular model (Lebeau et al., 2001), 6-OHDA-induced Parkinsonism model (Mu et al., 2009). The current study was the first to explore into the neuropharmacological function of baicalein in motor deficiency and biochemical changes in QA-induced HD rats, which appear to expand neurophysiological modifications in the rat brain's striatum, that can be seen using haematoxylin and eosin staining. Some experiments also indicate that the small dimeric protein BDNF, has been decreased due to the pathogenic mechanism of HD development, regulates corticostriatal synapse function (Zuccato and Cattaneo, 2007). GDNF has a similar survival-promoting role on motor neurons, and helps to regulate the motor cognitive deficits in the brain that have worsened in HD patients (Jordi Alberch et al., 2004).

By inducing QA intrastriatal administration in Wistar rat striatum, we were able to show that BC had a potential neuroprotective effect against HD-like symptoms, thus mimicking neuropathological and neurochemical hallmarks. Finally, this work can be used to untangle the previously unknown property of BC in relation to HD.