Parkinson’s disease is the second most common progressive neurodegenerative disease diagnosed mainly based on clinical symptoms caused by loss of nigrostriatal dopaminergic neurons. Although currently available pharmacological therapies provide symptomatic relief, however, the disease continues to progress eventually leading to severe motor and cognitive decline and reduced quality of life. The hallmark pathology of Parkinson’s disease includes intraneuronal inclusions known as Lewy bodies and Lewy neurites, including fibrillar α-synuclein aggregates. These aggregates can progressively spread across synaptically connected brain regions leading to emergence of disease symptoms with time. The α-synuclein level is considered important in its fibrillization and aggregation. Nucleic acid therapeutics have recently been shown to be effective in treating various neurological diseases, raising the possibility of developing innovative molecular therapies for Parkinson’s disease. In this review, we have described the advancements in genetic dysregulations in Parkinson’s disease along with the disease-modifying strategies involved in genetic regulation with particular focus on downregulation of α-synuclein gene using various novel technologies, notably antisense oligonucleotides, microRNA, short interfering RNA, short hairpin RNAs, DNA aptamers, and gene therapy of vector-assisted delivery system-based therapeutics. In addition, the current status of preclinical and clinical development for nucleic acid-based therapies for Parkinson’s disease have also been discussed along with their limitations and opportunities.
An interdisciplinary discipline called maritime archaeology studies human cultures' submerged cultural legacy. India offers tremendous opportunities for marine archaeology study due to its extensive coastline and maritime heritage. To strengthen India's security measures, this article discusses the relevance of maritime archaeology in India and emphasizes the urgent necessity for a specialized marine forensic laboratory. The numerous facets of marine archaeology are covered in the research, along with their historical significance, archaeological methods, and national security concerns. The need to create a marine forensic lab to investigate crimes involving India's undersea cultural treasures and improve maritime security is further emphasized.
Background:
Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second
messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels
of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly
PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation.
Methods:
Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days
at a dose of 500 µg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue.
Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated
oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals.
Results:
The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also
enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide
levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression
in a dose-dependent manner, which LPS up-regulated.
Conclusion:
Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.
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