Rosmarinic acid attenuates lipopolysaccharide-induced neuroinflammation and cognitive impairment in rats

Highlights

• Rosmarinic acid (RA) improved the LPS-induced memory deficit.

• RA could prevent hippocampal neural cell loss through non-amyloidogenic pathways.

• RA attenuated brain inflammation and reversed oxidant-antioxidant balance.

• RA prevented the overproduction of TNF-α, IL-1β, and IL-6 in rat brain.

• RA could reverse the hippocampal and cortical levels of MDA, NOx, and SOD.

Abstract

It has been recently demonstrated that rosmarinic acid (RA) through modulation in the amyloidogenic pathway exhibit neuroprotective potential in Alzheimer’s disease. However, its effects on non-amyloidogenic pathways such as neuroinflammation (NI) and oxidative stress have not been elucidated carefully. Hence, this study aimed to investigate the effect of RA on cognitive function, cortical and hippocampal oxidant-antioxidant balance, and proinflammatory cytokines production in lipopolysaccharide (LPS)-induced NI in rats. NI was induced by intracerebroventricular injection of LPS (50 μg/20 μL; 10 μL into each ventricle) in Wistar rats. RA (25 and 50 mg/kg.) was intraperitoneally administrated to the experimental groups 30 min before the LPS injection and continued once per day for seven days. Cognitive function was investigated by the Y-maze test, and the production of proinflammatory cytokines and oxidative stress markers were evaluated in their hippocampi (HIP) and prefrontal cortex (PFC). In addition, neuronal damage was evaluated in the HIP subfields histologically. The RA administration could alleviate cognitive impairments caused by NI in LPS-treated rats as evidenced by improved working memory and attenuated neuronal injury in the HIP subfields. RA treatment in a dose-dependent manner prevented the overproduction of tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6 in both the HIP and PFC. RA significantly alleviated the HIP and PFC levels of malondialdehyde (MDA) and nitric oxide (NOx) and enhanced the superoxide dismutase (SOD) activity. These findings demonstrated that RA could also exert its neuroprotective effects by modulating non-amyloidogenic pathways such as inflammation and oxidative stress.

Introduction

Neuroinflammation (NI) is one of the most common denominators in several neurodegenerative diseases. Therefore, in recent years, the role of inflammatory processes in the etiology of many neurological disorders has been studied (Gilhus and Deuschl, 2019). Consequently, a bulk of evidence is rising attention and pointing to the role of NI in the pathophysiology of several neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (Dorothée, 2018). NI is an inflammatory response of the central nervous system (CNS) mediated by abnormal secretion of proinflammatory cytokines, chemokines, and reactive oxygen/nitrogen species (DiSabato et al., 2016). It can lead to an ongoing pathologic process in the CNS by infiltration of peripheral immune cells, edema, neuronal atrophy, damage, and death overtime. These events affect neuronal structure and function during prolonged NI, resulting in cognitive and functional impairments (Chen et al., 2016). Considering that, modulation of the immune system has emerged as a therapeutic strategy in neurodegenerative diseases (Chen et al., 2016). In this approach, valuable signs of progress are being made as several studies show considerable promise for new substances, mainly natural products. However, more in vivo experiments are still needed to improve our understanding of these substances' mechanisms of action (Rekatsina et al., 2020).

Rosmarinic acid (RA) is naturally found in the Lamiaceae family, such as rosemary, sage, lemon balm, mint, and sweet basil (Nadeem et al., 2019). The accumulating evidence supporting that RA exerts powerful neuroprotective, antimicrobial, anti-inflammatory, anti-aging, and antioxidant effects (Ma et al., 2020; Nadeem et al., 2019). However, its mechanisms of action have not been completely elucidated. For example, a recently published study demonstrated that RA by increasing brain monoamines such as norepinephrine, dopamine, and levodopa could suppress amyloid-beta aggregation in a mouse model of AD (Hase et al., 2019). Since NI, as a key pathological event, triggers and perpetuates several neurodegenerative diseases such as AD, its modulation could influence other pathological mechanisms linked to the neurodegenerative process (Batista et al., 2019). Therefore, we hypothesized that RA probably could affect other pathological mechanisms involved in AD like NI and oxidative stress. Consequently, this study aimed to broaden current knowledge of mechanisms through which RA impacts neurodegenerative diseases' pathogenesis. To test the hypothesis, we established a rat model of NI by intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) and evaluated RA's possible anti-NI efficiency in systemic administration.