Sitagliptin Attenuates the Cognitive Deficits in L-Methionine-Induced Vascular Dementia in Rats

Abstract

Vascular dementia (VaD) is the second most prevalent type of dementia characterized by progressive cognitive deficits and is a major risk factor for the development of Alzheimer’s disease and other neurodegenerative disorders. This study is aimed at determining the potential neuroprotective effect of sitagliptin (STG) on cognitive deficits in L-methionine-induced VaD in rats and the possible underlying mechanisms. 30 adult male Wistar albino rats were divided equally ( n = 10 ) into three groups: control, VaD, and VaD + STG groups. The cognitive performance of the animals was conducted by open field, elevated plus maze, Y-maze, novel object recognition, and Morris water maze tests. Serum homocysteine, TNF-α, IL-6, IL-10, total cholesterol, and triglycerides levels were assessed together with hippocampal MDA, SOD, and BDNF. Histopathological and immunohistochemical assessments of the thoracic aorta and hippocampus (CA1 region) were also performed. Chronic L-methionine administration impaired memory and learning and induced anxiety. On the other hand, STG protected against cognitive deficits through improving oxidative stress biomarkers, inflammatory mediators, lipid profiles, and hippocampus level of BDNF as well as decreasing caspase-3 and GFAP and increasing Ki-67 immunoreactions in the hippocampus. Also, STG improved the endothelial dysfunction via upregulation of aortic eNOS immunoreaction. STG improved the cognitive deficits of L-methionine-induced VaD by its antioxidant, anti-inflammatory, antiapoptotic, and neurotrophic effects. These findings suggest that STG may be a promising future agent for protection against VaD.

Treadmill Exercise Prevents Recognition Memory Impairment in VD rat model through Enhancement of Hippocampal Structural Synaptic Plasticity

“…As the disease progresses, patients experience progressive memory loss and emotional disorder in daily life, including communication disorder and anxiety [28][29] . In vivo study also confirms impaired discrimination index in recognition memory test [30] , which is one of the most common paradigms to assess hippocampal-dependent memory, including short-term recognition memory and long-term recognition memory [31] . In general, short-term memory only refers to the short-term storage of information, whereas long-term memories are required for remembering information [32] .…”

Experimentally induced animal models for cognitive dysfunction and Alzheimer's disease

“…Methionine model of AD: Treatment with L-methionine dramatically increases serum homocysteine levels and elevated homocysteine levels have been linked to oxidative stress and changes in the structure and function of cerebral blood vessels, both of which are important contributors to cerebral vascular dysfunction. It is known that oxidative stress and vascular dysfunction play a significant role in the pathology of AD and vascular dementias [43 , 44] . Memory acquisition and retrieval are significantly impaired in AD due to structural abnormalities in the cerebral capillaries, which also cause neuronal malfunction and death [44] Additionally, it has been demonstrated that hyperhomocysteinemia is neurotoxic [43] .…”

“…It is known that oxidative stress and vascular dysfunction play a significant role in the pathology of AD and vascular dementias [43 , 44] . Memory acquisition and retrieval are significantly impaired in AD due to structural abnormalities in the cerebral capillaries, which also cause neuronal malfunction and death [44] Additionally, it has been demonstrated that hyperhomocysteinemia is neurotoxic [43] . This neurotoxicity is due to an excess of N-methyl-D-aspartate receptors, elevated oxidative stress, increased cholinesterase activity, tau phosphorylation and the toxicity caused by amyloid-β peptides [44] .…”

“… Methionine Male Wistar albino rats aged 3 months Cholinergic deficits, endothelial dysfunction, neuroinflammation, gliosis, cognitive deficits, oxidative stress 1.7g/kg per day p.o for 32 days 1.7 g/kg per day p.o. for 8 weeks [43 , 44] 12. Okadaic (OKA) acid Male/female Sprague-Dawley rats aged 2-3months Tau phosphorylation, Amyloid β plaques, oxidative stress, cognitive deficits.…”

Blood levels of circulating methionine components in Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis

“…In addition to being required for protein biosynthesis, Met is metabolized to generate metabolites that play key roles in a number of cellular functions (Dash et al, 2016). Although few studies have focused on blood Met levels in humans, some associations have been shown between rat models of cognitive impairment and Met levels (Alzoubi et al, 2022;Khodir et al, 2022). Met is the sole substrate of Met adenosine transferase (MAT) for SAM synthesis, whereas SAM is a universal methyl donor for various methyl transfer reactions, including the methylation of DNA, RNA, and neurotransmitters in all organisms (Selhub et al, 2010).…”