{"id":232,"date":"2025-04-04T11:24:31","date_gmt":"2025-04-04T11:24:31","guid":{"rendered":"https:\/\/iins-prod.onlinecreation.pro\/?post_type=buni_events&p=232"},"modified":"2025-04-04T11:26:19","modified_gmt":"2025-04-04T11:26:19","slug":"seminar-kenneth-l-madsen","status":"publish","type":"buni_events","link":"http:\/\/iins.u-bordeaux.fr\/en\/events\/seminar-kenneth-l-madsen\/","title":{"rendered":"Seminar – Kenneth L. Madsen"},"content":{"rendered":"

Venue: Centre Broca<\/strong><\/p>\n

\n

Kenneth L. Madsen<\/a><\/strong><\/p>\n

Department of Neuroscience<\/a>\u00a0 \"\"
\n University of Copenhagen <\/a><\/p>\n

Invited by David Perrais (IINS)<\/p>\n

Title<\/h3>\n

A peripherally restricted PICK1 inhibitor for treatment of chronic pain<\/strong><\/p>\n

Abstract<\/h3>\n

Kathrine L. Jensen1,2<\/sup>,\u00a0Sara E. Jager2<\/sup>, Carolyn M. Goddard2<\/sup>, Marco Kowenicki1<\/sup>, Andreas T. S\u00f8rensen1,2<\/sup>, Kenneth L. Madsen1,2<\/sup><\/p>\n

1<\/sup> Zyneyro, H\u00f8rsholm, Denmark<\/p>\n

2<\/sup>Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience,\u00a0University of Copenhagen, Denmark<\/p>\n

Worldwide 1.5 billion people suffer from chronic pain. Whereas pain is crucial for our survival,\u00a0maladaptive\u00a0pain serves no biological function, and\u00a0leads\u00a0to comorbidities such as anxiety, depression, poor sleep, and high prescription drug use. We have developed\u00a0and characterized\u00a0a bivalent lipid-conjugated peptide,\u00a0mPD5,\u00a0designed to bind to the PDZ domain of the scaffold protein PICK1\u00a0(Protein Interacting with C-kinase 1).\u00a0mPD5\u00a0relieves both ongoing and evoked hypersensitivity in multiple mouse models of pain in\u00a0both\u00a0female and male mice.\u00a0Current treatment options for chronic pain entail severe dose-limiting side effects originating from their\u00a0action on the CNS. However,\u00a0we have data suggesting that\u00a0the distribution of\u00a0mPD5\u00a0is restricted to peripheral tissues.\u00a0Clearing of brain and spinal column tissue of mice injected with labelled mPD5 in combination with mass spectrometry data of brain tissue, spinal cord tissue, plasma, and CSF of mice injected with unlabelled mPD5 indicate that mPD5 is peripherally restricted. mPD5\u00a0was\u00a0present in dorsal root ganglions (DRGs) and plasma,\u00a0but undetected in CSF, spinal cord, or brain. While\u00a0PICK1 is well described in the CNS,\u00a0we lack knowledge\u00a0about\u00a0the role\u00a0of\u00a0PICK1 in the PNS. By extracting mRNA data from a publicly accessible database, we have confirmed the presence of PICK1 along the somatosensory nociceptive pathway of both human and mouse, including DRGs. In addition,\u00a0we have\u00a0used\u00a0mPD5\u00a0mimicking peptides\u00a0to\u00a0successfully\u00a0pull down PICK1 from both spinal cord and DRG tissue\u00a0from\u00a0male and female\u00a0humandonors,\u00a0substantiating that PICK1 is indeed a relevant therapeutic pain target in humans as well. Lastly, other peripherally acting drugs such as\u00a0botox,\u00a0lidocaine patches,\u00a0and capsaicin patches lead to impaired acute nociception. We have used a hot water tail immersion test (49\u00a0o<\/sup>C) and a capsaicin paw-lick\u00a0test revealing normal sensory perception of mice treated with mPD5. Relieving chronic pain, without limiting the sensitivity to potential harmful stimuli of everyday life would be a great benefit for patients. In conclusion, mPD5\u00a0alleviates\u00a0hypersensitivity\u00a0through\u00a0a novel mechanism\u00a0offering a unique option for further\u00a0investigation\u00a0that could provide valuable\u00a0insight into\u00a0the\u00a0biology\u00a0of pain.<\/p>\n

Selected publications<\/h3>\n
    \n
  • Fadahunsi N et al. (2024) Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. Science Advances 10:eadg2636.<\/li>\n
  • Jensen KL et al. (2024) Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models. JCI Insight 9<\/li>\n
  • Andersen RC et al. (2022) Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis. J Clin Invest 132<\/li>\n
  • Christensen NR, Pedersen CP, Sereikaite V, Pedersen JN, Vistrup-Parry M, S\u00f8rensen AT, Otzen D, Teilum K, Madsen KL, Str\u00f8mgaard K (2022) Bidirectional protein\u2013protein interactions control liquid\u2013liquid phase separation of PSD-95 and its interaction partners. iScience 25<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"

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