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

Abstract

IntroductionIntracerebroventricularly (icv) injected streptozotocin (STZ) is a widely used model for sporadic Alzheimer’s disease (sAD)-like pathology, marked by oxidative stress-mediated pathological progression. Intermittent theta burst stimulation (iTBS) is a noninvasive technique for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for several neurological diseases, including AD. The present study aims to investigate the effect of the iTBS protocol on the animal model of STZ-induced sAD-like pathology in the context of antioxidant, anti-inflammatory, and anti-amyloidogenic effects in the cortex, striatum, hippocampus, and cerebellum.MethodsMale Wistar rats were divided into four experimental groups: control (icv normal saline solution), STZ (icv STZ—3 mg/kg), STZ + iTBS (STZ rats subjected to iTBS protocol), and STZ + Placebo (STZ animals subjected to placebo iTBS noise artifact). Biochemical assays and immunofluorescence microscopy were used to evaluate functional and structural changes.ResultsThe icv STZ administration induces oxidative stress and attenuates antioxidative capacity in all examined brain regions. iTBS treatment significantly reduced oxidative and nitrosative stress parameters. Also, iTBS decreased Aβ-1-42 and APP levels. The iTBS enhances antioxidative capacity reported as elevated activity of its enzymatic and non-enzymatic components. In addition, iTBS elevated BDNF expression and attenuated STZ-induced astrogliosis confirmed by decreased GFAP+/VIM+/C3+ cell reactivity in the hippocampus.DiscussionOur results provide experimental evidence for the beneficial effects of the applied iTBS protocol in attenuating oxidative stress, increasing antioxidant capacity and decreasing reactive astrogliosis in STZ-administrated rats.

Sustained Systemic Antioxidative Effects of Intermittent Theta Burst Stimulation beyond Neurodegeneration: Implications in Therapy in 6-Hydroxydopamine Model of Parkinson’s Disease

“…This activation could reduce the damage caused by oxidative stress and protect brain tissue. Consistent with these findings, our previous studies have shown that Nrf2 is increased after iTBS treatment [21]. Furthermore, brain-derived neurotrophic factor (BDNF), which is known for its role as a modulator of synaptic plasticity, has been shown to induce the nuclear translocation of Nrf2.…”

“…Furthermore, brain-derived neurotrophic factor (BDNF), which is known for its role as a modulator of synaptic plasticity, has been shown to induce the nuclear translocation of Nrf2. In our previous study, we found an increased protein expression of BDNF after 21 days of iTBS stimulation in 6-OHDA-induced PD [21,23]. Collectively, these factors could contribute to the observed enhancement in the general state of oxidative balance.…”

“…Building on our previous results showing recovery of motor performance and positive effects on emotional behavior, learning, and memory as well as decreased histopathological signs and neuroinflammation in a 6-OHDA-induced SNpc degeneration paradigm of PD [23], our present study extends the therapeutic benefits of iTBS. Furthermore, iTBS treatment in other neurodegeneration models, such as streptozotocin (STZ)-induced Alzheimer's-like disease and trimethyltin (TMT)-induced Alzheimer's-like disease, demonstrated a significant reduction in oxidative stress markers and increased antioxidant capacity [17,21]. One possible explanation for the observed improvement in the general oxidation status after iTBS lies in the nuclear transcription factor E2-related factor 2 (Nrf2), which is recognized as a central player in managing the oxidative stress response.…”

“…Intermittent theta burst stimulation (iTBS) is a specialized rTMS protocol that elicits an LTP-like increase in cortical excitability, and is proving to be an attractive and superior choice for neuromodulatory treatments in clinical disorders, mainly due to the rapid onset of modulatory effects compared to conventional rTMS [16]. In addition, our team's research has demonstrated the marked efficacy of iTBS in attenuating inflammation and oxidative stress in various models of neurodegenerative disease [17][18][19][20][21]. However, the precise effects of iTBS on oxidative stress parameters in the context of PD remain largely unexplored.…”