scholarly journals Neuroprotective Activity of Sitagliptin via Reduction of Neuroinflammation beyond the Incretin Effect: Focus on Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Michał Wiciński ◽  
Eryk Wódkiewicz ◽  
Maciej Słupski ◽  
Maciej Walczak ◽  
Maciej Socha ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Experimental Studies ◽  
Interleukin 10 ◽  
Experimental Models ◽  
Neuroprotective Activity ◽  
Inflammatory Factors ◽  
Interleukin 17

Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), IL-17 (interleukin-17), and CD-163 (cluster of differentiation 163), and contributed to an increase in levels of anti-inflammatory factors: IL-10 (interleukin-10) and TGF-β (transforming growth factor β). Moreover, sitagliptin demonstrated antioxidative and antiapoptotic properties by modifying glutamate and glutathione levels within the region of hippocampus in mice. It has been observed that sitagliptin decreases accumulation of β-amyloid within encephalon structures in experimental models of Alzheimer’s dementia. This effect may be connected with SDF-1α (stromal cell-derived factor 1α) concentration. Administration of sitagliptin caused a significant improvement in MMSE (Mini–Mental State Examination) tests used for assessment of dementias. The paper presents potential mechanisms of sitagliptin activity in conditions connected with neuroinflammation with special emphasis on Alzheimer’s disease.

scholarly journals The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

2019 ◽  
Vol 240 (2) ◽  
pp. R47-R72 ◽  
Author(s):  
Lenka Maletínská ◽  
Andrea Popelová ◽  
Blanka Železná ◽  
Michal Bencze ◽  
Jaroslav Kuneš
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
The Elderly ◽  
Experimental Models ◽  
New Drugs ◽  
Neuroprotective Effects ◽  
The Impact

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

scholarly journals Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1

2016 ◽  
Vol 37 (6) ◽  
pp. 1959-1970 ◽  
Author(s):  
Panayiota Papadopoulos ◽  
Xin-Kang Tong ◽  
Hans Imboden ◽  
Edith Hamel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Mouse Model ◽  
Cognitive Deficits ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Transforming Growth Factor Β1 ◽  
Cerebrovascular Reactivity ◽  
Cerebrovascular Function

Alterations of the renin-angiotensin system have been implicated in the pathogenesis of Alzheimer's disease. We tested the efficacy of losartan (10 mg/kg/day for three months), a selective angiotensin II type 1 receptor antagonist, in alleviating cerebrovascular and cognitive deficits in double-transgenic mice (six months at endpoint) that overexpress a mutated form of the human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of the transforming growth factor-β1, thereafter named A/T mice. Losartan rescued cerebrovascular reactivity, particularly the dilatory responses, but failed to attenuate astroglial activation and to normalize the neurovascular uncoupling response to sensory stimulation. The cognitive deficits of A/T mice were not restored by losartan nor were the increased brain levels of soluble and insoluble Aβ1–40 and Aβ1–42 peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease mouse model of combined Aβ-induced vascular oxidative stress and transforming growth factor-β1-mediated vascular fibrosis. These data suggest that losartan may be promising for restoring cerebrovascular function in patients with vascular diseases at risk for vascular dementia or Alzheimer's disease. However, a combined therapy may be warranted for rescuing both vascular and cognitive deficits in a multifaceted pathology like Alzheimer's disease.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer’s disease risk

2008 ◽  
Vol 115 (6) ◽  
pp. 863-867 ◽  
Author(s):  
O. Combarros ◽  
P. Sánchez-Juan ◽  
J. A. Riancho ◽  
I. Mateo ◽  
E. Rodríguez-Rodríguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Disease Risk ◽  
Interleukin 10

The active form of glycogen synthase kinase-3? is associated with granulovacuolar degeneration in neurons in Alzheimer's disease

2002 ◽  
Vol 103 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Allal Boutajangout ◽  
Karelle Leroy ◽  
Authelet M. ◽  
Brian Anderton ◽  
Jean-Pierre Brion ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Active Form ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Granulovacuolar Degeneration

Neuroprotective Activity of the Methanolic Extract of Indigofera aspalathoides against Scopalamine induced Alzheimer's Disease in Experimental Rats

2021 ◽  
pp. 5163-5168
Author(s):  
Rajaram C. ◽  
S. Nelson Kumar ◽  
S. S. Sheeba Tabassum ◽  
Manohar R. ◽  
Sumanjali C.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traditional Medicine ◽  
Methanolic Extract ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Neuroprotective Activity ◽  
Control Group ◽  
Histological Structure ◽  
Anticancer Activities

The plant Indigofera aspalathoides is a traditional medicine with tremendous therapeutic potential which finds it use in treatment of various ailments such as antibacterial, antioxidant, anti-inflammatory, antidiabetic, and anticancer activities. There are no reports that related to the use of this plant in treating patients with Alzheimer’s disease (AD). Hence present study was aimed to scientifically evaluate the neuroprotective effect of the methanolic extract of Indigofera aspalathoides against scopalamine induced Alzheimer’s disease in experimental rats using behavioral tests like elevated plus maze, Y-maze, and rota-rod tests. In addition to this, biochemical evaluation for acetylcholinesterase activity and histopathological evaluation of brain were done. The results suggests that methanolic extract Indigofera aspalathoides (200mg/kg B.wt and 400mg/kg B.wt) used in this study shows significant improvement of various behavioral parameters like locomotion, anxiety, memory, motor integrity and coordination etc when compared to control group. MEIA inhibited brain AChE enzyme, thereby elevating Ach concentration in brain homogenate and ultimately improved memory of rats. Further, more or less normal histological structure of the hippocampus and all amyloid plaques and neurofibrillary tangles that are formed under the influence of scopolamine disappeared in the rats pretreated with MEIA (200mg/kg B.wt and 400mg/kg B.wt). It can be concluded that our results strongly support the anti-Alzheimer’s potential of the methanolic extract of the plant I.aspalathoides and its use in traditional medicine.

Altered expression of transforming growth factor-beta in Alzheimer's disease

Neurology ◽  
1995 ◽  
Vol 45 (8) ◽  
pp. 1561-1569 ◽  
Author(s):  
K. C. Flanders ◽  
C. F. Lippa ◽  
T. W. Smith ◽  
D. A. Pollen ◽  
M. B. Sporn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Altered Expression ◽  
Growth Factor Beta

scholarly journals A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Junkai Hu ◽  
Stanley Li Lin ◽  
Melitta Schachner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document