AUTHOR=Sá Santos Sónia , Santos Sara M. , Pinto Antónia R. T. , Ramu Vasanthakumar G. , Heras Montserrat , Bardaji Eduard , Tavares Isaura , Castanho Miguel A. R. B. TITLE=Amidated and Ibuprofen-Conjugated Kyotorphins Promote Neuronal Rescue and Memory Recovery in Cerebral Hypoperfusion Dementia Model JOURNAL=Frontiers in Aging Neuroscience VOLUME=8 YEAR=2016 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2016.00001 DOI=10.3389/fnagi.2016.00001 ISSN=1663-4365 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.