Department of Pharmacology

Our laboratory research interests focus on:

1) We are investigating the molecular mechanism through which ischemia generates the lower urinary tract symptoms (overactive bladder, benign prostatic hyperplasia and underactive bladder）, sexual dysfunction and testicular dysfunction（Saito M et al. Neurourol Urodyn 2012, Saito M et al. Sci Rep 2014, Shimizu S et al. Int J Urol 2014, Shimizu S et al. Int J Urol 2016, Shimizu S et al. Eur J Pharmacol 2020, Shimizu S et al. Life Sci 2021a, 2021b, Shimizu S et al. Eur J Pharmacol 2022.）.
We are also investigating the brain mechanism in hypertension-related urinary disorders.(Shimizu S et al. Br J Pharmacol 2018, Shimizu S et al. Neurourol Urodyn 2019)。
Moreover, psychological stress or strain is known to play an important role in the induction of urinary frequency and lower urinary tract symptoms including the overactive bladder and painful bladder syndrome/interstitial cystitis. However, the pathophysiological mechanism underlying the stress causing urinary frequency is not well understood. In our laboratory, the molecular mechanism on how psychological stress related neurotransmitters affect the urination is under investigation (Shimizu T et al. J Pharmacol Exp Ther 2016, Shimizu T et al. Br J Pharmacol 2017, Shimizu Y et al., Biochem Biophy Res Commun 2021, Hata Y et al. Biochem Biophy Res Commun 2022).

2) Microglia are the resident immune cells in the central nervous system. Under normal physiological conditions, microglia are characterized by ramified morphology and occupy their own territory, which make it convenient to monitor the microenvironment in their territory. On the other hand, microglia become activated in response to neuronal injury following brain ischemia and trauma. The activated microglia can exhibit either protective or detrimental function depending on their activation state (classical activation and alternative activation）. Recently, microenvironment has been suggested to play roles in the regulation of microglial activation state. But mechanism underlying microenvironment-regulated microglial activation is not fully understood. In our laboratory, we have been examining the roles of extracellular zinc in the microglial activation and function（Higashi Y et al. Sci Rep 2017, Aratake T et al. Metallomics 2018, Ueba Y et al. Biochem Biophys Res Commun 2018）.

3) Stress responses, the body’s responses to stress stimuli, are essential for adaptation to stress. On the other hand, prolonged or excessive activation of the responses could contribute to the development of stress-related disorders including hypertension and depression. Stress-related information is conveyed to the brain, which recruits neuronal and neuroendocrine systems for induction of stress responses. Therefore, focusing on the brain, we have been examining the central regulation mechanisms of stress responses in order to create novel therapeutical strategies for the stress-related diseases（Nakamura K et al. Sci Rep 2014, Higashi Y et al. Br J Pharmacol 2018）.

4) Alzheimer’s disease (AD) is one of the most popular diseases among the age-related diseases, however, the effective drug are not developed right now. We recently found the synthetic peptides possessing the proteolytic activity termed as Catalytide against amyloid beta peptide suggesting Catalytide may be new strategic peptide drug for AD. We are now investing the pre-clinical tests such as the effects against AD know-in mouse and stability of Catalytide (Nakamura R et al. Peptides 2019, Nakamura R et al. Integrative Molecular Medicine 2019, Nakamura R et al. J Royal Sci 2019）.

1. Molecular mechanism and new treatment strategy for lower urinary tract symptoms and sexual dysfunction

We have previously demonstrated that the decreased pelvic blood flow could cause detrusor overactivity, benign prostatic hyperplasia and erectile dysfunction using animal models. At present, we are investigating intensively the precise molecular mechanism by employing a pharmacological approach. Moreover, we are investigating the effect of intra-cerebroventricularlly administered stress-related neurotransmitters on the rat urodynamic parameters.

2. Molecular mechanism and new preventive strategy for sequelea of inflammatory brain disorders

In mammalian brain, zinc is present in a subset of glutamatergic axon terminals throughout the forebrain, especially in the hippocampus. Under severe conditions such as cerebral ischemia, excessive amount of zinc stored in presynaptic glutamatergic neurons is released into the extracellular space. We have previously demonstrated extracellular zinc is a novel trigger for microglial activation, and revealed zinc-induced microglial activation signaling pathway. At present, we are investigating the roles of zinc-activated microglia in sequelae of inflammatory brain disorders.

3. Novel therapeutical strategies for the stress-related diseases developed by prolonged or excessive activation of stress responses

Focusing on the sympatho-adrenomedullary system, an essential mechanism for adaptation to stress, we have been examining central regulation mechanisms of the system activated by stress-related neurotransmitters. In general, the sympatho-adrenomedullary system can regulate blood pressure and micturition. That’s why we have been also examining central mechanisms of stress-induced hypertension and urinary bladder dysfunction focusing on the regulation mechanisms of the sympatho-adrenomedullary system.

4. Application of Catalydide (catalytic peptide) for treatment and prevention of Alzheimer’s disease

We have recently reported about the novel finding that the shorter synthetic peptide possessed the auto-proteolytic activity and cleaved the amyloid-beta. Therefore, we termed Catalytide (Catalytic Peptide) as the general name of proteolytic peptide. This finding is the very interesting because the Catalytide is the most attractive candidate for the prevention and treatment of Alzheimer’s disease.