Neuroprotective effect of the standardised extract of Bacopa monnieri (BacoMind) in valproic acid model of autism spectrum disorder in rats

Mishra, Abhishek; Singla, Rubal; Kumar, Rohit; Rupa, Joshi; Sarma, Phulen; Kaur, Gurcharan; Raj, Sarma Amit; Prajapat, Manisha; Bhatia, Anju; Ramprasad, Pallola; Medhi, Bikash

doi:10.1016/j.jep.2022.115199

Cited by 23 publications

(18 citation statements)

References 74 publications

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“…To further explore the therapeutic effect of FUS + BDNFp-CMBs on autistic rats, we used Nissl staining to observe the morphology of PFC neurons in the four groups of rats. The results showed that the cell bodies of neurons in the PFC in the VPA group became smaller and the nuclei became pyknotic, highlighting neuron damage in this brain region of autistic rats, which was highly consistent with the previous research results ( Abhishek et al, 2022 ). After treatment, a small part of the damaged neurons in the PFC of the BDNFp group recovered, and in the FUS + BDNFp-CMBs group, the damaged neurons in the PFC recovered completely.…”

Section: Discussionsupporting

confidence: 92%

“…In the control group, the neuronal cell bodies in the PFC were in normal morphology. In the VPA group, the neuronal cell bodies in the PFC were significantly smaller and the nuclei were pyknotic, indicating neuronal damage in this brain region in autistic rats ( Abhishek et al, 2022 ). After treatment, some neurons in the PFC of the BDNFp group recovered to a normal shape, but there were still many damaged neurons; in the FUS + BDNFp-CMBs group, most of the neurons in the PFC returned to normal, both in terms of cell body size and nuclear size.…”

Section: Resultsmentioning

confidence: 98%

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Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model

Shen

Sun

et al. 2022

Front. Neurosci.

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Autism has clinical manifestations such as social interaction disorder, speech and intellectual development disorder, narrow interest range, and stereotyped and repetitive behavior, all of which bring considerable economic and mental burden to society and families, and represent a public health problem requiring urgent attention. Brain-derived neurotrophic factor (BDNF) plays an important role in supporting survival, differentiation, growth, and synapse formation of neurons and participates in the plasticity of nerves. However, it is difficult for BDNF to penetrate the blood-brain barrier (BBB) due to its large molecular weight. Low-frequency focused ultrasound (FUS) combined with microbubbles (MBs) has been demonstrated to be a promising method for opening the BBB non-invasively, transiently, and locally. Here, we studied the therapeutic effect of FUS combined with BDNF plasmid-loaded cationic microbubbles (BDNFp-CMBs) in a rat model of autism. BDNF-CMBs were prepared and the transfection efficiency of FUS combined with BDNF-CMBs was tested in vitro. A rat model of autism was established from the juvenile male offspring of Sprague-Dawley (SD) pregnant rats treated with sodium valproate (VPA) solution through intraperitoneal injection. The autism rats were randomized into three groups: the VPA group, which received no treatment, the BDNFp group, which was treated by injection of BDNFp, and the FUS + BDNFp-CMBs group, which was administered FUS combined with BDNFp-CMBs. Age-matched normal rats served as the control group (Con). Following treatment, stereotyped, exploratory, and social–behavioral tests were performed on the animals in each group. The rat brains were then collected for subsequent histological examination, and the changes in synaptic structures in the prefrontal cortex (PFC) were detected under transmission electron microscopy. The results showed that the constructed BDNFp could be loaded onto CMBs with high loading efficiency. The BDNFp-CMBs prepared in this study showed good stability in vivo. FUS combined BDNFp-CMBs could effectively and non-invasively open the BBB of rats. The stereotyped, exploratory, and social behaviors of the FUS + BDNFp-CMBs group were significantly improved. Compared to the VPA group, the abnormality of neuronal morphology and number in the PFC of the FUS + BDNFp-CMBs was alleviated to a certain extent and was accompanied by restoration of the damaged synapses in the encephalic region. Our work demonstrates the positive therapeutic effect of BDNF delivered by FUS non-invasively across the BBB into the PFC in a rat model of autism, offering a potential strategy for treating autism.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 98%

Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model

Shen

Sun

et al. 2022

Front. Neurosci.

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“…The oxidative stress response is a keystone in neuroinflammation, despite the latter being considered the major cause of ASD. , Oxidative stress has been associated with mitochondrial dysfunction found in autism. Over the years, the relatedness of oxidative stress with the pathophysiology of autism has become well established . ASD patients due to their low plasma and cellular reduced glutathione levels are considered to be more vulnerable to oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…The upregulation of the glutamate receptors such as AMPA and NMDA causes excitotoxin release, which in turn causes glutamate accumulation. In addition to this, data from both the preclinical and clinical studies suggest modulations in the AMPA, receptors as a target for ASD treatment. − In addition, activation of the glia may also catalyze the NMDA-mediated toxicity caused by the release of interleukins suggesting neuroinflammation-induced excitotoxicity in the neuron. ,, The abnormalities in cytokines released in the peripheral blood of the patients with ASD have also been documented. − Different studies have reported a rise in the cytokine profile of IL-1β, IL-6, TNF-α, and IL-10 in the ASD population. − Furthermore, levels of brain-derived neurotrophic factor (BDNF) have frequently been seen to be altered in the adult brains of ASD patients with a strong expression of this neurotrophic factor in the prefrontal cortex (PFC) and hippocampus of these ASD people. , It has been speculated that the alteration in BDNF levels in the brain regions contributing to the high degree of plasticity may be responsible for the behavioral changes associated with ASD. , Thus, a drug that permeates the blood–brain barrier (BBB) and potentially targets the excitatory glutamate toxicity along with significant anti-inflammatory action in brain is the need of hour.…”

Section: Introductionmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains

Mishra

Singla

Kumar

et al. 2022

ACS Chem. Neurosci.

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Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the in-silico method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.

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“…The three-chamber test (also known as Crawley’s sociability and preference for social novelty test) was performed as published [ 40 , 41 , 42 ] using a clear polyvinyl chloride (PVC) apparatus (60 × 40 × 20 cm) with three compartments (20 × 40 × 20 cm). For habituation, a mouse was placed in the central compartment and allowed to freely explore all three compartments for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice

Singla

Mishra

Lin

et al. 2022

IJMS

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Approximately 50–80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1+/−) reduced the Bmal1 protein levels by ~50–75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1+/− mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.

show abstract

Neuroprotective effect of the standardised extract of Bacopa monnieri (BacoMind) in valproic acid model of autism spectrum disorder in rats

Cited by 23 publications

References 74 publications

Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model

Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model

Granulocyte Colony-Stimulating Factor Improved Core Symptoms of Autism Spectrum Disorder via Modulating Glutamatergic Receptors in the Prefrontal Cortex and Hippocampus of Rat Brains

Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice

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