PI3K/AKT/mTOR Signalling Inhibitor Chrysophanol Ameliorates Neurobehavioural and Neurochemical Defects in Propionic Acid-induced Experimental Model of Autism in Adult Rats

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.

Download Full-text

PI3K/AKT/mTOR Signalling Inhibitor Chrysophanol Ameliorates Neurobehavioural and Neurochemical Defects in Propionic Acid-induced Experimental Model of Autism

10.21203/rs.3.rs-705335/v1 ◽

2021 ◽

Author(s):

Aarti Sharma ◽

Sidharth Mehan

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Blood Plasma ◽

Rat Brain ◽

Forced Swim Test ◽

Brain Homogenate ◽

Autism Spectrum ◽

Pathological Changes ◽

And Oxidative Stress ◽

Mtor Signalling

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social-communication deficits and repetitive behaviour. Several studies have revealed that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays an important role in the pathogenesis of autism. The PI3K/AKT/mTOR signalling pathway overexpression produces neurological abnormalities by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a natural substance derived from the plant Rheum palmatum, a well-known Chinese herbal remedy with potential pharmacological applications. The purpose of this study was to look into the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological changes in ICV-PPA-induced autism-like rats, with a particular emphasis on its effect on PI3K/AKT/mTOR downregulation in the brain. Furthermore, we looked at how CPH affected the levels of myelin basic protein (MBP) in rat brain homogenate, as well as apoptotic markers such caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were examined for behavioural abnormalities, like neuromuscular dysfunction using actophotometer, motor coordination by beam crossing task (BCT), depressive behaviour with forced swim test (FST), cognitive deficit, and consolidation of memory using Morris water maze (MWM) task. Prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms in PPA-treated rats. In addition, cellular, molecular, cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators have been examined in rat brain homogenates, blood plasma, and CSF samples. The current findings suggest that CPH also restores the altered neurochemical levels and potentially prevents autism-like gross pathological changes, including demyelination volume in the rat brain.

Download Full-text

Silica nanoparticles mediated neuronal cell death in corpus striatum of rat brain: implication of mitochondrial, endoplasmic reticulum and oxidative stress

Journal of Nanoparticle Research ◽

10.1007/s11051-014-2664-z ◽

2014 ◽

Vol 16 (11) ◽

Cited By ~ 16

Author(s):

Arshiya Parveen ◽

Syed Husain Mustafa Rizvi ◽

Farzana Mahdi ◽

Sandeep Tripathi ◽

Iqbal Ahmad ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Silica Nanoparticles ◽

Rat Brain ◽

Corpus Striatum ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

And Oxidative Stress

Download Full-text

Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/8725354 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Alfonso Díaz ◽

Samuel Treviño ◽

Jorge Guevara ◽

Guadalupe Muñoz-Arenas ◽

Eduardo Brambila ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Inflammatory Response ◽

Temporal Cortex ◽

Energy Drink ◽

Brain Regions ◽

Adult Rats ◽

Mechanisms Of Toxicity ◽

The Brain ◽

And Oxidative Stress

Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats.

Download Full-text

IGF-1/GLP-1 Signaling Activator 4-hydroxyisoleucine (4-HI) Prevent Neurobehavioral and Neurochemical Defects in Methylmercury-induced Experimental Model of ALS: Insights From CSF, Blood Plasma and Brain Homogenate Samples in Rats

10.21203/rs.3.rs-721622/v1 ◽

2021 ◽

Author(s):

Ambika Shandilya ◽

Sidharth Mehan

Keyword(s):

Cell Death ◽

Blood Plasma ◽

Motor Neuron ◽

Myelin Basic Protein ◽

Rat Brain ◽

Basic Protein ◽

Brain Homogenate ◽

Glutamate Excitotoxicity ◽

Specific Cell ◽

Dependent Manner

Abstract Amyotrophic lateral sclerosis (ALS) is the most prevalent adult motor neuron disease, characterized by progressive neuromuscular atrophy, heterogeneous muscle wasting, weakness, and behavioural despair-like symptoms, which are frequently associated with cognitive impairments. The neuropathological hallmarks of MeHg-induced ALS include oligodendrocyte destruction, myelin basic protein (MBP) depletion, and white matter degeneration, which ultimately leads to demyelination and motor neuron death. Numerous research studies have demonstrated that IGF-1/GLP-1 signaling dysregulation plays a significant role in ALS progression as it triggers programmed neuronal cell death, myelin sheath destruction, demyelination, glutamate excitotoxicity, pro-inflammatory cytokine release, and neuroinflammation. 4-hydroxyisoleucine (4-HI) is a unique bioactive amino acid derived from Trigonella foenum graecum, with insulin-mimetic and insulin-sensitizing properties in animal models. The objective of this study was to explore the neuroprotective potential of 4-HI on behavioural, molecular, neurochemical, and gross pathological alterations in MeHg-treated ALS-like rats, with a particular focus on its influence on IGF-1/GLP-1 upregulation in the brain. Furthermore, we investigated the effect of 4-HI on the concentration of myelin basic protein (MBP) in rat brain homogenate and CSF, and specific cell death markers such as caspase-3, Bax, and Bcl-2 in rat brain homogenate and blood plasma samples. In order to investigate the neurobehavioral abnormalities, rats were evaluated for muscular strength via the grip strength test (GST), locomotor deficits using open-field task (OFT), depressive behaviour with forced swim test (FST), and spatial learning in the Morris water maze (MWM) task. Chronic oral treatment with 4-HI at doses of 50 mg/kg and 100 mg/kg was given from days 22nd to 42nd of the experimental protocol to alleviate ALS-like symptoms in the MeHg model of rats. In addition to cellular, molecular, apoptotic, and neuroinflammatory assessments, neurotransmitter levels and oxidative stress indicators were examined in rat brain homogenates. The results of this study consistently show that 4-HI increases the level of neurotrophic growth factors such as IGF-1 and GLP-1 restores the altered neurochemical levels, and potentially prevents ALS-like gross pathological anomalies, including demyelination volume in the rat brain in a dose-dependent manner.

Download Full-text