Polypharmacological Potential of Phosphodiesterase 5 Inhibitors for the Treatment of Neurocognitive Disorders.

The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aß deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.

Phosphodiesterase 5 inhibitor mirodenafil ameliorates Alzheimer-like pathology and symptoms by multimodal actions.

BACKGROUND: Alzheimer's disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-ß (Aß) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties. METHODS: To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/ß-catenin signaling. RESULTS: Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aß and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aß through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3ß (GSK-3ß) activity, GR transcriptional activity, and the Wnt/ß-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/ß-catenin signaling. CONCLUSIONS: These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3ß kinase activity, GR signaling, and the Wnt/ß-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent.

Ten Most Important Things to Know About Caring for Transgender Patients.

Transgender people have a gender that is not in agreement with their birth sex. Previous barriers, including lack of provider knowledge, have created significant healthcare disparities for this population. Recent societal changes are increasing the numbers of transgender people seen by primary care practitioners. Ten key principles are provided to help primary care practitioners create more welcoming environments and provide quality care to transgender patients. Overall, all members of the healthcare team (primary and specialty) need to become aware of the transition process and maintain communication regarding risks, benefits, and goals. Transwomen (aka male to female) can be treated with estrogens, antiandrogens, or a combination. Benefits include change in fat distribution, skin softening, and breast development. Significant risks for thrombosis from estrogens have been linked to genetic mutations, smoking, prolonged inactivity, and hormone formulation. Oral administration may provide increased risk over peripheral administration. Transmen (aka female to male) can be treated with peripheral testosterone preparations. Benefits include deepening of voice and development of facial and body hair with variable changes in muscle mass. Risks from testosterone appear to be less common than from estrogen. Laboratory monitoring can guide treatment decisions and provide early detection of some complications. Monitoring of "existing" anatomy (either hormonally or surgically created or removed) is an important component of healthcare for transgender patients. Primary care providers also should be aware of resources in their community and online, which can help patients optimize their transition.

Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine.

Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.