Cucurbitacin B exerts neuroprotection in a murine Alzheimer’s disease model by modulating oxidative stress, inflammation, and neurotransmitter levels

Abstract

Background: Alzheimer's disease (AD) type dementia encompasses diverse cognitive deficits marked by free radicals and proinflammatory cytokines mediated progressive neurodegeneration and vascular damage including the blood-brain barrier. Subsequently, an imbalance in neurotransmitters, excitotoxicity, and synaptic loss provide impetus to AD pathogenesis and perpetuate brain dysfunctions. Cucurbitacin possesses several biological properties and has shown potential in cancer, diabetes, and brain disorders. In this study, neuroprotective effects of cucurbitacin B (CuB) were investigated using the intracerebroventricular streptozotocin (STZ-ICV) AD prototype. Methods: Wistar rats (adult males) were injected STZ-ICV (3 mg/kg) bilaterally on day(s) 1 and 3. Rats were treated with CuB (25, 50 mg/kg, i.p.) or donepezil (1 mg/kg, i.p.) for 28 days daily starting from day 1. Behavioral tests viz. locomotor activity, motor coordination, and memory functions were conducted at different time intervals. After behavioral tests, biochemical markers of oxidative mutilation, inflammatory cell demise, and neurotransmitters were assessed in the whole brain. Results: CuB attenuated STZ-ICV-induced decrease in spatial memory in novel object recognition task and long-term memory in passive avoidance test. CuB diminished protein carbonyls, lipid peroxidation, 8-hydroxy-2'-deoxyguanosine, and enhanced antioxidants in the brain of rats inoculated with STZ-ICV. A decline in inflammatory and cell death biomarkers was observed in rats treated with CuB and STZ-ICV. In neurotransmitter analysis, a decrease in acetylcholinesterase activity and glutamate levels indicated an increase in cholinergic and attenuation of excitatory transmission in the brain. GABA (γ-aminobutyric acid) levels were enhanced by CuB treatment in the STZ-ICV rat model. Histomorphometry analysis disclosed that CuB treatment caused an increase in viable neuron density in the cortex and hippocampus of rats against STZ-ICV neurotoxicity. Conclusions: It can be inferred that CuB can afford a decline in AD symptoms. CuB protects neurons against STZ-ICV toxicity that improved memory functions in rats.

Intermittent theta burst stimulation attenuates oxidative stress and reactive astrogliosis in the streptozotocin-induced model of Alzheimer’s disease-like pathology

“…Intracerebroventricular injection of STZ induces pathological changes at molecular, cellular, and behavioral levels—similar to those observed in the sporadic form of AD ( Salkovic-Petrisic et al, 2013 ; Grieb, 2016 ). Upon central application, STZ generates central insulin resistance resulting in glucose hypometabolism, mitochondrial damage, and the generation of intracellular oxidative and nitrosative stress ( Liu et al, 2022 ). It has been demonstrated that STZ promotes oxidative/nitrosative stress in rat brains detected as early as 1 week post-application and was present even 8 weeks following the acute application, suggesting ongoing degenerative processes ( Sharma and Gupta, 2001 ; Ishrat et al, 2006 ; Pathan et al, 2006 ; Shoham et al, 2007 ; Saxena et al, 2011 ; Alluri et al, 2020 ; Akhtar et al, 2021 ).…”

“…These results confirm that icv STZ induces chronic degenerative changes coupled with oxidative imbalance, not only in the structures related to learning and memory processes, but in virtually all examined brain regions. It has been shown that STZ-induced oxidative stress can directly trigger lipid peroxidation resulting in increased levels of MDA ( Farbood et al, 2020 ), as well as the change in the methylation pattern of DNA, leading to a cascade of neurodegenerative events marked by an increased 8OHdG level ( Liu et al, 2022 ). On the other hand, antioxidative mechanisms have been shown to be significantly impaired in STZ-administrated rats, mostly noted in the cortex and hippocampus region ( Alluri et al, 2020 ; Bavarsad et al, 2020 ; Akhtar et al, 2021 ; Liang et al, 2021 ; Tiwari et al, 2021 ).…”

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

“…Our in vivo observations were also confirmed by postmortem assessment of oxidative stress and an overall increase of lipid peroxidation was observed in AD-T2D animals, when compared with AD alone. It should be noted that oxidative stress alters lipid-lipid interaction leading to impaired membrane permeability [ 76 ] and high levels of markers of oxidative stress-induced lipid peroxidation and cytotoxicity such as 4-hydroxynonenal, MDA or thiobarbituric acid reactive substances are increased in AD [ 77 , 78 ] and diabetes [ 79 , 80 ] supporting a synergistic effect when both diseases coexist. In addition, lipid peroxidation is accompanied by structural and functional alterations of the microvasculature [ 69 ], that may ultimately contribute to the observed pathology when AD and T2D coexist.…”

The Supplementation of Sechium edule var. nigrum spinosum (Chayote) Promotes Nrf2-Mediated Antioxidant Protection in Older Adults with Metabolic Syndrome

“…Concerning cucurbitacins, their chemoprotective and antioxidant capacity has been shown [44][45][46]. Specifically, cucurbitacins I, D, B, and E can promote the expression of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO-1), which are phase II detoxification enzymes; the mechanisms proposed implies the regulation of the Nrf2 transcription factor, which in turn modulates the expression of SOD, GPx, and CAT.…”