BOTOX® counteracts the innate anxiety-related behaviours in correlation with increased activities of key antioxidant enzymes in the hippocampus of ageing experimental mice.

Cholinergic crisis and oxidative stress in the hippocampus of the brain have been known to induce anxiety disorders upon ageing. BOTOX® is a widely used therapeutic form of botulinum neurotoxin that acts by inhibiting the release of acetylcholine (ACh) from the nerve terminals at the neuromuscular junction. BOTOX® can migrate from the muscle to the brain through retrograde axonal transport and modulate neuroplasticity. While a mild dose of BOTOX® has been used to manage various neurological deficits and psychiatric complications including depression, the efficacy and experimental evidence for its anxiolytic effects and antioxidant properties remain limited. In this study, we have investigated the effect of BOTOX® on the innate anxiety-like behaviours in ageing mice upon exposure to different behavioural paradigms like open field test, elevated plus maze and light-dark box test, and estimated the enzymatic activities of key antioxidants in the hippocampus. Results revealed that animals injected with a mild intramuscular dosage of BOTOX® showed reduced level of innate anxiety-related symptoms and increased activities of hippocampal antioxidant enzymes compared to the control group. This study strongly supports that BOTOX® could be implemented to prevent or treat anxiety and hippocampal oxidative stress resulting from ageing, emotional and mood disorders.

Intramuscular Injection of BOTOX® Boosts Learning and Memory in Adult Mice in Association with Enriched Circulation of Platelets and Enhanced Density of Pyramidal Neurons in the Hippocampus.

BOTOX® is a therapeutic form of botulinum neurotoxin. It acts by blocking the release of acetylcholine (ACh) from the synaptic vesicles at the neuromuscular junctions, thereby inhibiting the muscle contraction. Notably, many neurological diseases have been characterized by movement disorders in association with abnormal levels of ACh. Thus, blockade of aberrant release of ACh appears to be a potential therapeutic strategy to mitigate many neurological deficits. BOTOX® has widely been used to manage a number of clinical complications like neuromuscular disorders, migraine and neuropathic pain. While the beneficial effects of BOTOX® against movement disorders have extensively been studied, its possible role in the outcome of cognitive function remains to be determined. Therefore, we investigated the effect of BOTOX® on learning and memory in experimental adult mice using behavioural paradigms such as open field task, Morris water maze and novel object recognition test in correlation with haematological parameters and histological assessments of the brain. Results revealed that a mild dose of BOTOX® treatment via an intramuscular route in adult animals improves learning and memory in association with increased number of circulating platelets and enhanced structural plasticity in the hippocampus. In the future, this minimally invasive treatment could be implemented to ameliorate different forms of dementia resulting from abnormal ageing and various neurocognitive disorders including Alzheimer's disease (AD).

The Regulation of Reactive Neuroblastosis, Neuroplasticity, and Nutraceuticals for Effective Management of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) encompasses a cluster of neurodevelopmental and genetic disorders that has been characterized mainly by social withdrawal, repetitive behavior, restricted interests, and deficits in language processing mainly in children. ASD has been known to severely impair behavioral patterns and cognitive functions including learning and memory due to defects in neuroplasticity. The biology of the ASD appears to be highly complex and heterogeneous, and thus, finding a therapeutic target for autism remains obscure. There has been no complete prevention or disease-modifying cure for this disorder. Recently, individuals with autism have been characterized by reactive neurogenesis, obstructions in axonal growth, heterotopia, resulting from dysplasia of neuroblasts in different brain regions. Therefore, it can be assumed that the aforementioned neuropathological correlates seen in the autistic individuals might originate from the defects mainly in the regulation of neuroblasts in the developing as well as adult brain. Nutrient deficiencies during early brain development and intake of certain allergic foods have been proposed as main reasons for the development of ASD. However, the integrated understanding of neurodevelopment and functional aspects of neuroplasticity working through neurogenesis in ASD is highly limited. Moreover, neurogenesis at the level of neuroblasts can be regulated by nutrition. Hence, defects in neuroblastosis underlying the severity of autism potentially could be rectified by appropriate implementation of nutraceuticals.

Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders.

The hippocampus-derived neuroestradiol plays a major role in neuroplasticity, independent of circulating estradiol that originates from gonads. The response of hypothalamus-pituitary regions towards the synthesis of neuroestradiol in the hippocampus is an emerging scientific concept in cognitive neuroscience. Hippocampal plasticity has been proposed to be regulated via neuroblasts, a major cellular determinant of functional neurogenesis in the adult brain. Defects in differentiation, integration and survival of neuroblasts in the hippocampus appear to be an underlying cause of neurocognitive disorders. Gonadotropin receptors and steroidogenic enzymes have been found to be expressed in neuroblasts in the hippocampus of the brain. However, the reciprocal relationship between hippocampal-specific neuroestradiol synthesis along neuroblastosis and response of pituitary based feedback regulation towards regulation of estradiol level in the hippocampus have not completely been ascertained. Therefore, this conceptual article revisits (1) the cellular basis of neuroestradiol synthesis (2) a potential relationship between neuroestradiol synthesis and neuroblastosis in the hippocampus (3) the possible involvement of aberrant neuroestradiol production with mitochondrial dysfunctions and dyslipidemia in menopause and adult-onset neurodegenerative disorders and (4) provides a hypothesis for the possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis in the adult brain. Eventually, understanding the regulation of hippocampal neurogenesis by abnormal levels of neuroestradiol concentration in association with the feedback regulation of HPH axis might provide additional cues to establish a neuroregenerative therapeutic management for mood swings, depression and cognitive decline in menopause and neurocognitive disorders.

Genetic reprogramming of somatic cells into neuroblasts through a co-induction of the doublecortin gene along the Yamanaka factors: A promising approach to model neuroregenerative disorders.

Neural stem cell (NSC) mediated adult neurogenesis represents the regenerative plasticity of the brain. The functionality of the neurogenic process appears to be operated by neuroblasts, the multipotent immature neuronal population of the adult brain. While neuroblasts have been realized to play a major role in synaptic remodeling and immunogenicity, neurodegenerative disorders have been characterized by failure in the terminal differentiation, maturation, integration and survival of newborn neuroblasts. Advancement in understanding the impaired neuroregenerative process along the neuropathological conditions has currently been limited by lack of an appropriate experimental model of neuroblasts. The genetic reprogramming of somatic cells into pluripotent state offers a potential strategy for the experimental modeling of brain disorders. Thus, the induced pluripotent stem cell (iPSC) based direct reprogramming of somatic cells into neuroblasts would represent a potential tool to understand the regenerative biology of the adult brain. Therefore, this concise article discusses the significance of iPSCs, the functional roles of neuroblasts in the adult brain and provides a research hypothesis for the direct reprogramming of somatic cells into neuroblasts through the co-induction of a potential proneurogenic marker, the doublecortin (DCX) gene along with the Yamanaka factors. The proposed cellular model of adult neurogenesis may provide us with further insights into neuropathogenesis of many neurodegenerative disorders and will provide a potential experimental platform for diagnostic, drug discovery and regenerative therapeutic strategies.