| 1. |
- Aso, Ester, et al.
(författare)
-
Poly(propylene imine) dendrimers with histidine-maltose shell as novel type of nanoparticles for synapse and memory protection.
- 2019
-
Ingår i: Nanomedicine: Nanotechnology, Biology, and Medicine. - : Elsevier BV. - 1549-9642 .- 1549-9634. ; , s. 198-209
-
Tidskriftsartikel (refereegranskat)abstract
- Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection.
|
|
| 2. |
- Benseny-Cases, Núria, et al.
(författare)
-
In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer’s disease transgenic mice using synchrotron-based infrared imaging
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer’s disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.
|
|
| 3. |
- López-Cano, Marc, et al.
(författare)
-
Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects
- 2023
-
Ingår i: British Journal of Pharmacology. - : John Wiley & Sons. - 0007-1188 .- 1476-5381. ; 180:7, s. 958-974
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo.Experimental Approach: Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms.Key results: In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal.Conclusion and Implications: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects.
|
|
| 4. |
- Valle-Leon, Marta, et al.
(författare)
-
Decreased striatal adenosine A2A-dopamine D2 receptor heteromerization in schizophrenia
- 2021
-
Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 46, s. 665-672
-
Tidskriftsartikel (refereegranskat)abstract
- According to the adenosine hypothesis of schizophrenia, the classically associated hyperdopaminergic state may be secondary to a loss of function of the adenosinergic system. Such a hypoadenosinergic state might either be due to a reduction of the extracellular levels of adenosine or alterations in the density of adenosine A(2A)receptors (A(2A)Rs) or their degree of functional heteromerization with dopamine D(2)receptors (D2R). In the present study, we provide preclinical and clinical evidences for this latter mechanism. Two animal models for the study of schizophrenia endophenotypes, namely the phencyclidine (PCP) mouse model and the A(2A)R knockout mice, were used to establish correlations between behavioural and molecular studies. In addition, a new AlphaLISA-based method was implemented to detect native A(2A)R-D2R heteromers in mouse and human brain. First, we observed a reduction of prepulse inhibition in A(2A)R knockout mice, similar to that observed in the PCP animal model of sensory gating impairment of schizophrenia, as well as a significant upregulation of striatal D2R without changes in A(2A)R expression in PCP-treated animals. In addition, PCP-treated animals showed a significant reduction of striatal A(2A)R-D2R heteromers, as demonstrated by the AlphaLISA-based method. A significant and pronounced reduction of A(2A)R-D2R heteromers was next demonstrated in postmortem caudate nucleus from schizophrenic subjects, even though both D2R and A(2A)R were upregulated. Finally, in PCP-treated animals, sub-chronic administration of haloperidol or clozapine counteracted the reduction of striatal A(2A)R-D2R heteromers. The degree of A(2A)R-D2R heteromer formation in schizophrenia might constitute a hallmark of the illness, which indeed should be further studied to establish possible correlations with chronic antipsychotic treatments.
|
|
