Intranasal AdipoRon mitigates motor and cognitive deficits in hemiparkinsonian rats through neuroprotective mechanisms against oxidative stress and synaptic dysfunction

Article

作者: Farajdokht, Fereshteh ; Alimohammadi, Soraya ; Mohaddes, Gisou ; Azizifar, Negin ; Athari, Seyed Zanyar ; Keyhanmanesh, Rana

While motor symptoms are the most well-known manifestation of Parkinson's disease (PD), patients may also suffer from non-motor signs like cognitive impairments. The adiponectin receptor agonist AdipoRon (Adipo) has shown neuroprotective effects in preclinical studies. The objective of this study was to determine the potential benefits of chronic intranasal treatment of Adipo on motor function and cognitive performance in a hemiparkinsonian rat model caused by injecting 6-hydroxydopamine (6-OHDA) into the left forebrain bundle. After one week, PD rats were given either a vehicle or one of three dosages of Adipo (0.1, 1, and 10 μg) or levodopa (10 mg/kg orally) daily for 21 days. Recognition and spatial memory were determined using the novel object recognition test (NORT) and the Barnes maze test, respectively. The hippocampal tissues of the animals were harvested to examine oxidative stress status as well as the protein expressions of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95). In hemiparkinsonian rats, motor impairments, recognition memory, and spatial memory were all improved by chronic intranasal Adipo at 1 and 10 μg. Furthermore, we found that unilateral 6-OHDA injection elevated hippocampal oxidative stress (ROS) while concurrently reducing total antioxidant capacity (TAC), BDNF, PSD-95, and antioxidant enzymes (SOD, GPx). However, Adipo 10 μg significantly reduced these biochemical alterations in the hippocampus of 6-OHDA-lesioned rats. Chronic intranasal Adipo ameliorated spatial and recognition memory deterioration in hemiparkinsonian rats, presumably by increasing hippocampal synaptic protein levels, reducing oxidative stress, and increasing BDNF.

2024-12-01·European Journal of Pharmacology

AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats

Article

作者: Mohaddes, Gisou ; Athari, Seyed Zanyar ; Azizifar, Negin ; Karimipour, Mohammad ; Farajdokht, Fereshteh ; Alimohammadi, Soraya ; Keyhanmanesh, Rana

The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH⁺) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH⁺ cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction.

2024-11-01·Free Radical Biology and Medicine

Diabesity alters the protective effects of estrogens on endothelial function through adipose tissue secretome

Article

作者: Proenza, Ana María ; Lladó, Isabel ; Valle, Adamo ; Morán-Costoya, Andrea ; González-Vicens, Agustí ; Amengual-Cladera, Emilia ; Martínez-Cignoni, Melanie Raquel ; Gianotti, Magdalena

Estrogens have a well-known protective role in the development of the metabolic syndrome. Nevertheless, recent epidemiological data question the cardioprotective effect of estrogens in obese and diabetic women. In this context, white adipose tissue (WAT) becomes dysfunctional, which has an impact on the cardiovascular system. The aim of the study was to elucidate the role of 17β-estradiol (E2) in the interplay between adipose tissue and endothelial function in an animal model of diabesity. We used ZDF (fa/fa) female rats subjected to ovariectomy (OVA), OVA + E2 or sham operated, as well as non-obese non-diabetic ZDF (fa/+) rats. Endothelial function and vascular remodeling markers were assessed in the aorta, while mitochondrial function, oxidative stress, and adiponectin production were analyzed in gonadal WAT. Conditioned media from gonadal WAT explants were used to assess the effects of WAT secretome on HUVEC. Additionally, the adiponectin receptor agonist AdipoRON and E2 were utilized to examine potential interactions. Ovariectomy ameliorated the WAT dysfunction associated to the obese and diabetic state and promoted adiponectin secretion, effects that were linked to a reduction of endothelial dysfunction and inflammatory markers in the aorta of OVA rats and in HUVEC treated with OVA-conditioned media. Our findings provide evidence supporting the idea that in the context of obesity and diabetes, ovariectomy improves WAT secretome and positively impacts endothelial function, suggesting a detrimental role for E2. Additionally, our results point to adiponectin as the primary driver of the effects exerted by ovariectomy on the adipovascular axis.

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适应症	最高研发状态	国家/地区	公司	日期
糖尿病心肌病	临床前	韩国	The Catholic University of Korea	2020-06-06
2型糖尿病肾脏病	临床前	韩国	The Catholic University of Korea	2017-10-31
2型糖尿病	临床前	日本	University of Tokyo	2013-10-30
肥胖	临床前	日本	University of Tokyo	2013-10-30