Scientists have been constantly looking for new synthetic and natural compounds that could have beneficial effects in bladder overactivity. Our attention was drawn by asiatic acid that influences a number of molecules and signaling pathways relevant for the proper functioning of the urinary tracts in humans. In the present project we wanted to check whether asiatic acid would have positive effects in the confirmed animal model of detrusor overactivity (DO) and whether it would affect the bladder blood flow, urothelium thickness, inflammatory and oxidative stress markers, neurotrophic and growth factors, and other parameters important for the activity of the urinary bladder. The outcomes of our study showed that a 14-day administration of asiatic acid (30 mg/kg/day) by oral gavage normalizes the cystometric parameters corresponding to DO and reduces the accompanying oxidative stress (measured by the levels of malondialdehyde-61,344 ± 24,908 pg/ml vs. 33,668 ± 5,071 pg/ml, 3-nitrotyrosine-64,615 ± 25,433 pg/ml vs. 6,563 ± 1,736 pg/ml, and NOS2-2,506 ± 411.7 vs. 3,824 ± 470.1 pg/ml). Moreover, it decreases the urinary secretion of neurotrophins (BDNF-304.4 ± 33.21 pg/ml vs. 119.3 ± 11.49 pg/ml and NGF-205.5 ± 18.50 vs. 109.7 ± 15.94 pg/ml) and prevents the changes in a range of biomarkers indicating the dysfunction of the urinary bladder, CGRP (421.1 ± 56.64 vs. 108.1 ± 11.73 pg/ml), E-Cadherin (773.5 ± 177.5 pg/ml vs. 1,560 ± 154.5 pg/ml), OCT3 (3,943 ± 814.6 vs. 1,018 ± 97.07 pg/ml), SNAP-23 (6,763 ± 808.9 pg/ml vs. 3,455 ± 554.5 pg/ml), SNAP-25 (2,038 ± 162.7 pg/ml vs. 833.3 ± 65.48), substance P (171.7 ± 16.86 pg/ml vs. 65.07 ± 8.250 pg/ml), SV2A (1,927 ± 175.3 pg/ml vs. 1,154 ± 254.9 pg/ml), tight junction protein 1 (360.1 ± 95.05 pg/ml vs. 563.4 ± 65.43 pg/ml), VAChT (16,470 ± 2,419 pg/ml vs. 7,072 ± 1,339 pg/ml), VEGFA (318.3 ± 37.89 pg/ml vs. 201.5 ± 22.91 pg/ml). The mentioned parameters are associated with smooth muscle contractions, urothelial barrier, transportation and release of transmitters, or bladder compensation. Thus, the presented findings allow to suggest a possible future role of asiatic acid in the prevention of conditions accompanied by DO, such as overactive bladder.

Memory impairment is one of the main complications of Alzheimer's disease (AD). This condition can be induced by hyper-stimulation of N-Methyl-D-aspartate receptors (NMDARs) of glutamate in the hippocampus, which ends up to pyramidal neurons determination. The release of neurotransmitters relies on voltage-gated calcium channels (VGCCs) such as P/Q-types. Omega-lycotoxin-Gsp2671e (OLG1e) is a P/Q-type VGCC modulator with high affinity and selectivity. This bio-active small protein was purified and identified from the Lycosa praegrandis venom. The effect of this state-dependent low molecular weight P/Q-type calcium modulator on rats was investigated via glutamate-induced excitotoxicity by N-Methyl-D-aspartate. Also, Electrophysiological amplitude of field excitatory postsynaptic potentials (fEPSPs) in the input-output and Long-term potentiation (LTP) curves were recorded in mossy fiber and the amount of synaptophysin (SYN), synaptosomal-associated protein, 25 kDa (SNAP-25), and synaptotagmin 1(SYT1) genes expression were measured using Real-time PCR technique for synaptic quantification. The outcomes of the current study suggest that OLG1e as a P/Q-type VGCC modulator has an ameliorative effect on excitotoxicity-induced memory defects and prevents the impairment of pyramidal neurons in the rat hippocampus.

Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.

Herein, we have evaluated the protective potentials of Fisetin against d-galactose-induced oxidative stress, neuroinflammation, and memory impairment in mice. d-galactose (D-gal) causes neurological impairment by inducing reactive oxygen species (ROS), neuroinflammation, and synaptic dysfunction, whereas fisetin (Fis) is a natural flavonoid having potential antioxidant effects, and has been used against different models of neurodegenerative diseases. Here, the normal mice were injected with D-gal (100 mg/kg/day for 60 days) and fisetin (20 mg/kg/day for 30 days). To elucidate the protective effects of fisetin against d-galactose induced oxidative stress-mediated neuroinflammation, we conducted western blotting, biochemical, behavioral, and immunofluorescence analyses. According to our findings, D-gal induced oxidative stress, neuroinflammation, synaptic dysfunctions, and cognitive impairment. Conversely, Fisetin prevented the D-gal-mediated ROS accumulation, by regulating the endogenous anti-oxidant mechanisms, such as Sirt1/Nrf2 signaling, suppressed the activated p-JNK/NF-kB pathway, and its downstream targets, such as inflammatory cytokines. Hence, our results together with the previous reports suggest that Fisetin may be beneficial in age-related neurological disorders.