Epilepsy affects around 50 million people across the globe and is the third most common chronic brain disorder. It is a non-communicable disease of the brain that affects people of all ages. It is accompanied by depression, anxiety, and substantially increased morbidity and mortality. A large number of third-generation anti-epileptic drugs are available, but they have multiple side-effects causing a decline in the quality of life. The inheritance and etiology of epilepsy are complex with multiple underlying genetic and epigenetic mechanisms. Different neurotransmitters play intricate functions to maintain the normal physiology of various neurons. If there is any dysregulation of neurotransmission due to aberrant transmitter levels or their receptor biology, it can result in seizures. In this review, we have discussed the roles played by various neurotransmitters and their receptors in the pathophysiology of epilepsy. Drug-resistant epilepsy (DRE) has remained one of the forefront areas of epilepsy research for a long time. Understanding the mechanisms underlying DRE is of utmost importance because of its high incidence rate among epilepsy patients and increased risks of psychosocial problems and premature death. Here we have enumerated various hypotheses of DRE. Further, we have discussed different non-conventional therapeutic strategies, including combination therapy and non-drug treatment. The recent studies supporting the modern approaches for the treatment of epilepsy have been deliberated with particular reference to the mTOR pathway, breakdown of the blood-brain barrier, and inflammatory pathways.

Parkinson's disease (PD) is a progressive, age-related neurodegenerative disease. The disease is characterized by the loss of dopaminergic neurons in the substantia nigra, pars compacta of the midbrain. Pramipexole (PPX) is a novel drug used for the treatment of PD. It has a high affinity for the dopamine (DA) D2 receptor subfamily and acts as a targeted mitochondrial antioxidant. It is less effective in the treatment of PD due to its short half-life, highly inconvenient dosing schedule, and long-term side effects. In recent years, PPX-loaded nanoformulations have been actively reported to overcome these limitations. In the current study, we focused on increasing the effectiveness of PPX by minimizing the dosing frequency and improving the treatment strategy for PD. Herein, we report the synthesis of biodegradable polyvinylpyrrolidone (PVP)-capped copper oxide nanoparticles (PVP-CuO NPs), followed by PPX anchoring on the surface of the PVP-CuO NPs (PPX-PVP-CuO NC), in a simple and inexpensive method. The newly formulated PPX-PVP-CuO NC complex was analyzed for its chemical and physical properties. The PPX-PVP-CuO NC was tested to protect against rotenone (RT)-induced toxicity in the Drosophila PD model. The in vivo studies using the RT-induced Drosophila PD model showed significant changes in negative geotaxis behavior and the level of DA and acetylcholinesterase. In addition, oxidative stress markers such as glutathione-S-transferase, total glutathione, thiobarbituric acid reactive species, and protein carbonyl content showed significant amelioration. The positive changes of PPX-PVP-CuO NC treatment in behavior, neurotransmitter level, and antioxidant level suggest its potential role in mitigating the PD phenotype. The formulation can be used for treatment or pharmacological intervention against PD.

In normal physiological conditions, reactive oxygen and nitrogen species are used as important signaling molecules in the cell. However, in excess it causes the disruption of cell resulting in their death. Oxidative stress causes influx in intracellular calcium levels leading to higher concentrations of calcium in the cell. This accelerated calcium affects both the mitochondria and nuclei leading to excitotoxicity in neurons. Intracellular calcium levels are controlled by voltage dependent calcium channels located in the plasma membrane, calcium stores like endoplasmic/sarcoplasmic reticulum and majorly by calcium binding proteins. Our study was aimed at analyzing the gene expression of major calcium binding proteins namely calcineurin, calmodulin, calreticulin, synaptotagamin and calsyntenin in stress induced PC 12 cells. Rotenone (1 μM), Peroxynitrite (10 μM), H2O2 (100 μM) and High glucose (33 mM) were used to induce oxidative stress in PC12 cells. Results obtained from the study suggest that calcineurin, calmodulin and calsyntenin gene expression were enhanced compared to the control due to oxidative stress. However, synaptotagmin and calreticulin gene expression were down regulated. Further, Akt protein expression (stress marker) was enhanced in PC12 cells with all other stress inducers except in hyperglycemic condition.

The blood‐brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface‐modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co‐modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.

Parkinson’s disease (PD) is the most common neurodegenerative disorder; in this condition, patients lose dopamine (DA), which leads to abnormal motor functions. Levodopa (LD) is the most effective drug used for the treatment of PD; however, LD shows poor plasma bioavailability and limited brain uptake and induces peripheral side effects. Due to its poor brain availability and short half-life, prolonged treatment must be repeated with a dosing schedule, which leads to long-term side effects, including dyskinesia, stomatitis, anxiety, and depression. An LD-encapsulated polymer nanocomposite has been reported to overcome these problems. The present study aims to improve the bioavailability and efficiency of LD to an effective treatment strategy for PD. Herein, we report the newly synthesized LD-encapsulated poly-ε-caprolactone (PCL) nanocomposite (LD-PCL-PVA NC), and its chemical and physical properties were analyzed. The LD-PCL-PVA NC exhibits no toxicity on the SH-SY5Y cell line and shows improved bioavailability of the LD in mouse plasma. Furthermore, we found that LD-PCL-PVA NC showed a significant improvement in motor symptoms in the rotenone (RT)-induced PD mouse model compared to the LD treatment. In addition, LD-PCL-PVA NC significantly increased the DA and homovanillic acid compared to LD and restored the total glutathione level and malonaldehyde and catalase activity in mouse brain. The histopathology studies reveal that LD-PCL-PVA NC did not exhibit toxicity in treated mice. The study suggested that LD-PCL-PVA NC can be used for the effective and promising treatment of PD.

Autoinhibitory domain (AID) of calcineurin (CN) was discovered two decades ago. Fewer investigations are reported to find out shortest possible peptide from the AID for CN inhibition. Hence, this study has focused on screening of nearly 150 peptide fragments derived from the AID using in silico method. Therefore, we have employed docking studies, aiming to analyze the best pose of AID-derived peptides on CN active site. We also analyzed binding free energy (ΔG) of docked complex using molecular mechanics/generalized Born surface area (MM/GBSA). MM/GBSA predicts two short peptides P1 and P2 found to be lowest binding free energy. Two peptides exhibit better binding affinity with CN, suggests that the possible candidates for potential CN inhibition. Further, the stability of the docked complex was analyzed using molecular dynamic (MD) simulation. MD study shows that CNA:P2 is the most stable complex than CN A:P1 and CN A:AID. Besides, we have synthesized and purified P1 and P2 peptides over high performance liquid chromatography (HPLC) found to be 90.31% and 98.93% of purity, respectively. In addition, AID peptides were characterized over mass spectral analysis. Peptides were subjected to CN inhibitory assay using malachite green method. Where, P1 and P2 exhibit CN inhibition better than AID. In particular, shortest peptide P2 shows highest inhibitory activity than AID. Enzyme assay reveals CN inhibitory activity of P2 peptide is consistent within silico results. In silico and in vitro, results corroborated each other to confirm short peptide P2 can be used as a potential CN inhibitor.