The Neuroprotective Action of Amidated-Kyotorphin on Amyloid β Peptide-Induced Alzheimer’s Disease Pathophysiology

Abstract

Kyotorphin (KTP, L-tyrosyl-L-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH 2 , when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid b peptide (Ab). Animals were treated for 20 days with KTP-NH 2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Ab administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH 2 treatment, Ab-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Ab-injected rats that

Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics

“…reversed the memory impairment in an i.c.v . amyloid-β peptide (Aβ)-induced sporadic AD model in rats and Aβ-induced decrease in the spine density in cortical neuronal cultures ( 62 ).…”

Compound dietary fiber and high-grade protein diet improves glycemic control and ameliorates diabetes and its comorbidities through remodeling the gut microbiota in mice

“…Soybean protein is a considerable source of L-arginine, and L-arginine has been regarded as a novel and effective therapy for obesity, diabetes, and metabolic syndrome. Kyotorphin is a unique biologically active neuropeptide (L-tyrosine-L-arginine), and it may exert an antidiabetic effect through its neuroprotective properties ( 42 ). In addition, a high serum level of betaine was associated with a low risk of T2D, and the supplementation of betaine improved insulin resistance in obese mice ( 43 ).…”

Neuroprotective effects of hawthorn leaf flavonoids in Aβ25–35‐induced Alzheimer's disease model

“…The accumulation of Aβ peptide is one of the pathological characteristics of AD, causing cognitive dysfunction, neuronal damage, and oxidative stress (Kim, Lee, Chung, Kim, & Kim, 2016). Aβ injection in the hippocampus of animals is one of the most relevant AD models due to it could mimic the AD pathophysiological characteristic induced by Aβ (Belo et al, 2020). As the shortest active fragment of Aβ, Aβ 25–35 exhibits a neurotoxicity effect similar to a full‐length Aβ in AD brains (Kaminsky, Marlatt, Smith, & Kosenko, 2010; Pike et al, 1995; Smith & Klimov, 2018).…”