Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 22, Issue 2, 2022

Background: The emergence of new diseases poses therapeutic challenges in modern medicine. Polyurethane hydrogels that comprise polyol, copolymer and extender could be prepared from diverse chemical compounds with adjuvants such as ascorbic acid and sorbitol, among others. Their mechano-physicochemical properties are functions of their biological activities. Therefore, there is a need to assess their therapeutic potentials. Methods: Relevant literature on the synthesis and medical uses of polyurethane-hydrogels, polyurethane- aerogels, and polyurethane-graphene nanocomposite materials was searched in order to identify their sources, synthesis, mechanical and physiochemical properties, biomedical applications, chirality, and the relevance of Lipinski's rule of five in the synthesis of oral polyurethane nanocomposite materials. Results: The prepared hydrogels and aerogels could be used as polymer carriers for intradermal, cutaneous, and intranasal drugs. They can be fabricated and used as prosthetics. In addition, the strength modulus (tensile stress-tensile strain ratio), biodegradability, biocompatibility, and nontoxic effects of the polyurethane hydrogels and aerogels are highly desirable properties. However, body and environmental temperatures may contribute to their instability; hence, there is need to improve the synthesis of aerogels and hydrogels of polyurethane in order to ensure that they can last for many years. Alcoholism, diabetes, pyrogenic diseases, mechanical and physical forces, and physiological variability may also reduce the life span of polyurethane aerogels and hydrogels. Conclusion: Synthesis of polyurethane hydrogel-aerogel complex that can be used in complex, rare biomedical cases is of paramount importance. These hydrogels and aerogels may be hydrophobic, hydrophilic, aerophobic-aerophilic or amphiphilic, and sometimes lipophilic, depending on structural components and the intended biomedical uses. Polyurethane graphene nanocomposite materials are used in the treatment of a myriad of diseases, including cancer and bacterial infection.

Background: Neuronal death underlies the symptoms of several human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis and their precise pathophysiology have not yet been elucidated. According to various studies, the prohibition is the best therapy with neuroprotective approaches, which are advanced and safe methods. Methods: This review summarizes some of the already-known and newly emerged neuroprotective targets and strategies and their experimental effects have also been reported. Accordingly, literature was studied from 2000 to 2021, and appropriate articles were searched in Google Scholar and Scopus with the keywords given in the keywords section of the current review. Results: Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and are protein-rich intracellular deposits in which Alpha-synuclein is its major protein. Alphasynuclein’s toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing its burden in neuronal cells through numerous pathways, including ubiquitin-proteasome system and autophagy-lysosome pathway, proteolytic breakdown via cathepsin D, kallikrein-6 (neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists of a target protein-ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination (PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau proteins and glycogen synthase kinase 3β; their accumulation proceeds extensive neuronal damage and up to the minute approach such as proteolysis targeting chimera promotes its degradation in cells. Various studies demonstrated that Mendelian gene mutations can result in neurodegenerative diseases. An additional target that has gained much interest is epigenetics, such as mutation, phosphodiesterase, RNA binding proteins and Nuclear respiratory factor 1. Conclusion: The novel molecular targets and new strategies compiled and introduced here can be used by scientists to design and discover more efficient small molecule drugs against neurodegenerative diseases. And also, the genes in which their mutations can lead to the α-synuclein aggregation or accumulation have been discussed and considered a valuable information on epigenetics in dementia.

Background: Chronic morphine stimulates prolonged stimulation of opioid receptors, especially μ-opioid subtype (MOR), which in turn signals cellular adaptation. However, the sudden termination of the use of morphine after chronic intake causes the withdrawal syndrome. Objectives: Hence, this study was designed to find an alternative treatment for morphine withdrawal using the alkaloid leaf extract of Erythroxylum cuneatum (E. cuneatum) for the treatment of morphine-exposed neuroblastoma cell lines. Methods: SK-N-SH, a commercialised neuroblastoma cell line, was used in two separate study designs; the antagonistic and pre-treatment of morphine. The antagonistic treatment was conducted through concurrent exposure of the cells to morphine and E. cuneatum or morphine and methadone for 24 hrs. The pre-treatment design was carried out by exposing the cells to morphine for 24 hrs, followed by 24 hrs exposure to E. cuneatum or methadone. The cytosolic fraction was collected and assessed for proteins expression involved in cellular adaptation, including mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase 1/2 (MEK 1/2), extracellular signalregulated kinase 2 (ERK 2), cAMP-dependent protein kinase (PKA) and protein kinases C (PKC). Results: The antagonistic treatment showed the normal level of MEK 1/2, ERK 2, PKA and PKC by the combination treatment of morphine and E. cuneatum, comparable to the combination of morphine and methadone. Neuroblastoma cells exposed to morphine pre-treatment expressed a high level of MEK 1/2, ERK 2, PKA and PKC, while the treatments with E. cuneatum and methadone normalised the expression of the cellular adaptation proteins. Conclusion: E. cuneatum exerted anti-addiction properties by lowering the levels of cellular adaptation proteins it’s effects is comparable to that of methadone (an established anti-addiction drug).

Background: Epileptic seizures are associated with the overproduction of free radicals in the brain leading to neuronal cell death. Therefore, reduction of oxidative stress may inhibit seizure- induced neuronal cell damage. The current study evaluated the effects of Vit D3 and melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice. Methods: Animals were divided into six groups. Group I was administered with normal saline (0.5 ml, intraperitoneally (i.p.)) on the 15th day of the experiment. Group II was injected with PTZ (60 mg/kg dissolved in 0.5 ml normal saline, i.p) on the 15th day. Groups III-IV were treated with diazepam (4 mg/kg/day), Vit D3 (6000 IU/kg/day), melatonin (20 mg/kg/day), and Vit D3 (6000 IU/kg/day)/melatonin (20 mg/kg/day), respectively, and were then injected with PTZ (60 mg/kg) on the 15th day of the experiment. Immediately after the injection of PTZ on the 15th day, mice were observed for a 30-min period to measure seizure latency and duration. For determination of oxidative stress markers, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured in mouse brains. Results: Treatment with Vit D3, melatonin, and Vit D3/melatonin significantly increased seizure latency and decreased seizure duration. The brain level of MDA was lower, and SOD activity was greater than in the PTZ group. Mice treated with Vit D3/melatonin had lower seizure duration than other treated groups. Conclusions: The combination of Vit D3 and melatonin may reduce seizure frequency in epileptic patients; this effect may result from various mechanisms, including inhibition of oxidative stress.

Background: There are over 500 species in the Passiflora genus, and while some of them are very well known in folk medicine for their anxiolytic effects, very little is known for the other genus representants, which could also present medicinal effects. Objective: In this study, we performed an interspecific pharmacological comparison of five investigated Passiflora species, all native to Brazil, namely P. bahiensis, P. coccinea, P. quadrangularis, P. sidaefolia, and P. vitifolia. Methods: Extracts were administered to mice before behavioral testing, including a general pharmacological screening and anxiolytic-like effect investigation. Results: Three of the species (P. coccinea, P. quadrangularis, and P. sidaefolia) induced a decrease in locomotor activity of mice; P. coccinea also reduced the latency to sleep. Importantly, none of the species interfered with motor coordination. Oral administration evoked no severe signs of toxicity, even at higher doses. Regarding the anxiolytic-like profile, P. sidaefolia reduced the anxious-like behavior in the Holeboard test in a similar way to the positive control, Passiflora incarnata, while not affecting total motricity. Conclusion: These results indicated that P. coccinea, P. quadrangularis, and P. sidaefolia reduced the general activity of mice and conferred a calmative/sedative potential to these three species, which must be further elucidated by future investigations.

Background: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters. Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs. Methods: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed. Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets. Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.