A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain

Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P$_4$‐(C5)$_2$, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P$_4$‐(C5)$_2$ disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P$_4$‐(C5)$_2$ administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P$_4$‐(C5)$_2$ as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains

Brief hospitalizations of elderly patients:a retrospective, observational study

BACKGROUND: Crowded departments are a common problem in Danish hospitals, especially in departments of internal medicine, where a large proportion of the patients are elderly. We therefore chose to investigate the number and character of hospitalizations of elderly patients with a duration of less than 24 hours, as such short admissions could indicate that the patients had not been severely ill and that it might have been possible in these cases to avoid hospitalization. METHODS: Medical records were examined to determine the number of patients aged 75 or more who passed through the emergency department over a period of two months, and the proportion of those patients who were discharged after less than 24 hours. The reasons for the hospitalization, the diagnoses and the treatment given were noted. RESULTS: There was a total of 595 hospitalizations of patients aged 75 or above in the emergency department during the period. Twenty-four percent of the older patients were discharged after less than 24 hours. Of these, 40% were discharged from the emergency department. The most common problems leading to hospitalization were change in contact or level of consciousness, focal neurological change, red, swollen or painful leg conditions, dyspnea, suspected parenchyma surgical disease and problems with the urinary system or catheters. The most common diagnoses given at hospital were chronic cardiovascular disease, bacterial infection, symptoms deriving from bone, muscle or connective tissue, liquid or electrolyte derangement and observation for suspected stroke or transient cerebral ischemia. Eight percent of the patients required telemetry, 27% received intravenous liquids, 30% had diagnostic radiology procedures performed and 3% needed invasive procedures. Other types of treatment given included electrocardiography, laboratory examinations, oxygen supplements, urinary catheterization and medicine administered orally, subcutaneously, as an intramuscular injection or as an inhalation. CONCLUSION: There appears to be a group of patients who cannot be adequately handled with the resources of the primary health care sector, yet who do not belong at the emergency department. Further studies are needed to create a suitable service for these patients, and to improve the continuity of the treatment and the cooperation between hospitals and the primary health care sector

Open Access

retrospective, observational stud

A high‐affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain

Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P$_4$‐(C5)$_2$, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P$_4$‐(C5)$_2$ disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P$_4$‐(C5)$_2$ administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P$_4$‐(C5)$_2$ as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains