title: Amidated and Ibuprofen-Conjugated Kyotorphins Promote Neuronal Rescue and Memory Recovery in Cerebral Hypoperfusion Dementia Model.
abstract: Chronic brain ischemia is a prominent risk factor for neurological dysfunction and progression for dementias, including Alzheimer's disease (AD). In rats, permanent bilateral common carotid artery occlusion (2VO) causes a progressive neurodegeneration in the hippocampus, learning deficits and memory loss as it occurs in AD. Kyotorphin (KTP) is an endogenous antinociceptive dipeptide whose role as neuromodulator/neuroprotector has been suggested. Recently, we designed two analgesic KTP-derivatives, KTP-amide (KTP-NH2) and KTP-NH2 linked to ibuprofen (IbKTP-NH2) to improve KTP brain targeting. This study investigated the effects of KTP-derivatives on cognitive/behavioral functions (motor/spatial memory/nociception) and hippocampal pathology of female rats in chronic cerebral hypoperfusion (2VO-rat model). 2VO-animals were treated with KTP-NH2 or IbKTP-NH2 for 7 days at weeks 2 and 5 post-surgery. After behavioral testing (week 6), coronal sections of hippocampus were H&E-stained or immunolabeled for the cellular markers GFAP (astrocytes) and NFL (neurons). Our findings show that KTP-derivatives, mainly IbKTP-NH2, enhanced cognitive impairment of 2VO-animals and prevented neuronal damage in hippocampal CA1 subfield, suggesting their potential usefulness for the treatment of dementia.
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa Lisboa, Portugal.
authors: Sónia
authors: S
authors: Sá Santos
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa Lisboa, Portugal.
authors: Sara M
authors: SM
authors: Santos
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa Lisboa, Portugal.
authors: Antónia R T
authors: AR
authors: Pinto
authors: Laboratori d'Innovació en Processos i Productes de Síntesi Orgànica, Departament de Química, Universitat de Girona Girona, Spain.
authors: Vasanthakumar G
authors: VG
authors: Ramu
authors: Laboratori d'Innovació en Processos i Productes de Síntesi Orgànica, Departament de Química, Universitat de Girona Girona, Spain.
authors: Montserrat
authors: M
authors: Heras
authors: Laboratori d'Innovació en Processos i Productes de Síntesi Orgànica, Departament de Química, Universitat de Girona Girona, Spain.
authors: Eduard
authors: E
authors: Bardaji
authors: Departamento de Biologia Experimental, Faculdade de Medicina do PortoPorto, Portugal; Instituto de Biologia Molecular e CelularPorto, Portugal; i3S - Instituto de Inovação e Investigação em Saúde, Universidade do PortoPorto, Portugal.
authors: Isaura
authors: I
authors: Tavares
authors: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa Lisboa, Portugal.
authors: Miguel A R B
authors: MA
authors: Castanho
keywords: 2VO-dementia model; chronic cerebral hypoperfusion; cognitive impairment; hippocampus; kyotorphin derivatives; neuroprotection