In this narrative review article, we discuss the role of sleep deprivation (SD) in memory processing in rodent models. Numerous studies have examined the effects of SD on memory, with the majority showing that sleep disorders negatively affect memory. Currently, a consensus has not been established on which damage mechanism is the most appropriate. This critical issue in the neuroscience of sleep remains largely unknown. This review article aims to elucidate the mechanisms that underlie the damaging effects of SD on memory. It also proposes a scientific solution that might explain some findings. We have chosen to summarize literature that is both representative and comprehensive, as well as innovative in its approach. We examined the effects of SD on memory, including synaptic plasticity, neuritis, oxidative stress, and neurotransmitters. Results provide valuable insights into the mechanisms by which SD impairs memory function.

Sleep disorders are the most widespread mental disorders after stroke and hurt survivors’ functional prognosis, response to restoration, and quality of life. This review will address an overview of the progress of research on the biological mechanisms associated with stroke-complicating sleep disorders. Extensive research has investigated the negative impact of stroke on sleep. However, a bidirectional association between sleep disorders and stroke exists; while stroke elevates the risk of sleep disorders, these disorders also independently contribute as a risk factor for stroke. This review aims to elucidate the mechanisms of stroke-induced sleep disorders. Possible influences were examined, including functional changes in brain regions, cerebrovascular hemodynamics, neurological deficits, sleep ion regulation, neurotransmitters, and inflammation. The results provide valuable insights into the mechanisms of stroke complicating sleep disorders.

Colorectal cancer is one of the most common malignancies, and the topoisomerase inhibitor irinotecan (CPT-11)-based chemotherapeutic regimen is currently the first-line treatment with impressive therapeutic efficacy. However, irinotecan has several clinically significant side effects, including diarrhea, which limit its clinical utility and efficacy in many patients. In an effort to discover better and improved pharmacotherapy against colorectal cancer, we synthesized a novel topoisomerase inhibitor, PCC0208037, examined its anti-tumor efficacy and related molecular mechanisms, and characterized its toxicity and pharmacokinetic profiles. PCC0208037 suppressed colorectal cancer cell (CRC) proliferation and increased cell cycle arrest, which may be related to its effects on up-regulating DNA damage response (DDR)-related molecules and apoptosis-related proteins. PCC0208037 demonstrated robust anti-tumor activity in vivo in a colorectal cancer cell xenograft model, which was comparable to or slightly better than CPT-11. In a preliminary toxicology study, PCC0208037 demonstrated much weaker tissue damage to colorectal tissue than CPT-11, and its impacts on food intake and body weight loss were more transient and recovered faster than CPT-11 in mice. This could be partially explained by the pharmacokinetic findings, which showed that PCC0208037 and its active metabolite, SN-38, were more accumulated in tumor tissue than in the intestine, as compared to CPT-11. Taken together, these results described a novel Topo I inhibitor with a comparative advantage over the standard treatment of colorectal cancer CPT-11 and could be a promising candidate compound for the treatment of colorectal cancer that warrants further investigation.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Zuranolone (SAGE-217), the first FDA-approved oral neurosteroid (NAS), a positive allosteric modulator (PAM) of γ-aminobutyric acid type A (GABA_A) receptor for postpartum depression approved in 2023, has limitations such as short half-life, low bioavailability, and central inhibitory side effects. To address these, we designed novel C-21 modified derivatives of Zuranolone, identifying the triazolone scaffold as key for enhancing GABA_A activity. Here, we synthesized Zuranolone analogs with diverse triazolone substituents, finding that pyridine-derived modifications improved the activity correlated with LogP. The optimal derivative, S9 (2-(trifluoroethoxy)pyridine-triazolone, LogP 4.61), showed 2.5-fold greater potency (EC₅₀) and efficacy (Emax) than Zuranolone (LogP 4.78) at synaptic/extrasynaptic GABA_A receptors, attributed to stronger binding via molecular docking. In rats, S9 exhibited 5-fold longer plasma T_1/2, 6-fold higher AUC, 3-fold greater brain exposure, and 30% improved bioavailability. It also outperformed Zuranolone in pentylenetetrazole (PTZ)-induced seizure suppression and threshold dose for loss of righting reflex (LORR) in rats. The C21-pyridine-triazolone pharmacophore in S9 enhances receptor activity potency without increasing lipophilicity, optimizing pharmacokinetics and safety, which makes it a promising therapeutic candidate for depression and epilepsy.

Compound 7–16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT_2A receptor antagonist and inverse agonist for treating Parkinson’s disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7–16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7–16/[¹⁴C]7–16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7–16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7–16 was at least 74.7%. 7–16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7–16 deserves further development as a new treatment drug for PDP.