CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 20, Issue 6, 2021

Alpha-synuclein (α-synuclein) is a protein that is abundantly found in the brain and in a lesser amount in the heart and muscles. The exact role of α-synucleinis is not known, but it is considered to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies that damage the dopaminergic neurons in the subtantianigra of the midbrain and leads to the progression of Parkinson’s Disease (PD). There are evidences showing that aggregates of α-synuclein behave like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

Parkinson’s Disease (PD) is one of the most prevalent, recurrent and life-threatening neurodegenerative diseases. However, the precise mechanism underlying this disease is not yet clearly understood. For understanding the pathogenesis of PD, it is essential to identify the symptoms along with the novel biological markers and to develop strategies that could lead towards the development of effective therapy. PD is associated with Lewy bodies (LBs) formation and the loss of dopaminergic neurons in the substantia nigra pars compacta of mid brain region. For the improvement in treatment strategies, as well as understanding the pathophysiology of the PD in a number of animal models have been introduced that can recapitulate the pathophysiology, motor and nonmotor symptoms of PD. In contrast to mammalian models like rodents, mice and monkey, Drosophila is easy to handle as well as its maintenance cost is low. Due to the anatomical differences in the brain and other major organs of human and fly, the issues of standardizing the methods or experiments to analyze behavioral aspects (walking, writhing, eating and sleeping) are difficult in flies. The present review highlights the studies carried out for PD since 2000, using Drosophila melanogaster.

Advances in the field of nanotechnology and nanomedicine have resulted in the development of novel diagnosis and potential treatment for different types of diseases, including brain cancer. Nanomaterials are smaller in size, having a higher area to volume ratio, and can be conjugated with other molecules. Nanomaterials are excellent transport vehicles that can easily cross the extracellular matrix, cell membrane, and by crossing the blood-brain barrier, they can deliver the drugs to the remote and inaccessible internal parts of the brain. A nanorobot is a device that ranges in size from 0.1-10 micrometer and resembles in size to a red blood cell. Nanorobot is a smart robot that can patrol the bloodstream, recognize the specific target, and can release a tiny but deadly cargo of drugs or nanoparticles to kill the cancer cells. With the multidisciplinary approach of biotechnology, molecular biology, electronics, bioinformatics-based computer simulation, and molecular medicine, a self-sufficient nanodevice can be developed for brain tumor diagnosis and treatment. This review article discusses the current applications and future promises of nanorobots in brain cancer therapy.

Background: Human health issues caused by Cigarette Smoke Carcinogens (CSC) are increasing rapidly every day and challenging the scientific community to provide a better understanding in order to avoid its impact on communities. Cigarette smoke also contains tobacco-based chemical compounds harmful to human beings, either smokers or non-smokers. Objective: We have tested 7H-Dibenzo[c,g]carbazole (7H-DBC) and Dibenz[a,h]acridine (DBAD) derivatives of Asz-arenes along with N'-Nitrosoanabasine (NAB) and N-Nitrosoanatabine (NAT) derivatives of N-Nitrosamines molecular interaction with CNS biomolecules. Methods: Computational synergistic approaches like system biology and molecular interaction techniques were implemented to conduct the analysis. Results: CSC efficiently interacted with NRAS, KRAS, CDH1, and RAC1 molecular targets in CNS. We have also performed the interactome analysis followed by system biology approaches and found that HSPA8 is the most important hub protein for the network generated for CSC-hampered genes of CNS. We have also identified 6 connector proteins, namely TP53, HSP90AA1, PPP2CA, CDH1, CTNNB1, and ARRB1. Further analysis revealed that NRAS and CDH1 have maximum interactions with all the selected CSC. Conclusion: The obtained structural analysis data could be utilized to assess the carcinogenic effect of CSC and could be useful in the treatment of CNS diseases and disorders induced, especially by tobacco-specific carcinogens, or it could also be used in vivo/ in vitro experimentation model designing.

Background: Gabapentin (GBP) is an FDA-approved drug for the treatment of partial and secondary generalized seizures, apart from being used for diabetic neuropathic pain. GBP displays a highly intricate mechanism of action and its inhibitory response in elevated antagonism of NMDA (N-methyl-D-aspartate receptor) receptor and thus, can be repurposed for controlling neuropathic pain. Objective: Therefore, in the present study, we have selected hBCATc (humanPyridoxal 5’-phosphate- dependent branched-chain aminotransferase cytosolic) gene that is highly expressed in silico validation through neuropathic stressed conditions. Thereafter, have analysed the GBP as its competitive inhibitor by in silico validation through homology modelling, molecular docking, also predicting its structural alerts and pharmacokinetic suitability through ADMET. However, and GBP was found to be a potential drug in controlling neuropathic pain, still, it has certain critical and pharmacokinetic limitations; therefore, the need for its targeted delivery was required, and the same was attained by designing a GBP loaded transdermal patch (GBP-TDP). Methods: A suitable and equally efficacious GBP - TDP was developed by a solvent evaporation method using PVP and HPMC in the ratio of 2:1 as a polymer base for reservoir type of TDP. Also, PEG 400 was used as a plasticizer, and PVA (4%) was taken for backing membrane preparation, and then the optimized GBP-TDP was subjected for physical characterization, optimization and ex vivo release kinetics. Results: The results showed desired specifications with uneven and flaky surface appearance giving an avenue for controlled release of the drugs with 92.34 ± 1.43% of drug release in 10 hours, further suggesting that GBP-TDP can be used as an effective tool against diabetic neuropathy pain. Conclusion: In this study, we have repurposed Gabapentin to treat diabetic neuropathy and validated the same by conducting a detailed in silico evaluation starting from homology Modelling of the target protein hBCATc, cross verified by the Ramachandran plot analysis with the most favoured region of 92.1% (encompassing 303 residues out of 386).