Tetramethylpyrazine Alleviates Behavioral and Psychological Symptoms of Dementia Through Facilitating Hippocampal Synaptic Plasticity in Rats With Chronic Cerebral Hypoperfusion.

Zihu Tan,Guangya Liu,Jia Li,Guang Yang,Yuting Zhang,Hengfei Li,Xixi Yin,Qiong Yang,Jing Qiu

doi:10.3389/fnins.2021.646537

Abstract

Behavioral and psychological symptoms of dementia (BPSD) ubiquitously disturb all patients with dementia at some point in the disease course. Although a plethora of non-pharmacological and pharmacological methods targeting the relief BPSD have been developed, the therapeutic effect is still far from ideal. Here, a rat BPSD model combining the physiological changes with mental insults was successfully established. Meanwhile, our results indicated that TMP attenuated anxious behavior using an elevated plus maze (EPM) test, ameliorated recognitive ability and sociability through a novel object recognition test (NORT) and social interaction test (SIT), and improved learning and memory impairments via a Barnes maze in rats with bilateral common carotid arteries occlusion (BCCAO) plus chronic restraint stress (CRS). Given that hippocampus chronic cerebral hypoperfusion (CCH) always causes damage to the hippocampus, and the majority of cognitive impairments, behaviors, and stress responses are associated with pathology in the hippocampus including anxiety and depression, we paid attention to investigate the role of the hippocampus in BPSD. Our results indicated that Tetramethylpyrazine (TMP) attenuated anxiety and ameliorated recognitive ability, sociability, learning, and memory impairments due to alleviating dendritic and spine deficits, and upregulating the expression of synapse-related proteins (including PSD95, SYN, GAP43, SYP) in the hippocampus. We also found that the underlying mechanism was that TMP could activate the TrkB/ERK/CREB signaling pathway to promote synaptic remodeling in vivo and in vitro. Mechanically, the present study enlarges the therapeutic scope of TMP in neurodegenerative disorders and provides basic knowledge and feasible candidates for treating BPSD, particularly for vascular dementia.

Highlights

Dementia is a progressive neurodegenerative disorder causing both functional and cognitive deficits (Cascade et al, 2008; Matthews et al, 2013)
Our results demonstrated that TMP substantially upregulated p-TrkB (Figure 9A), p-ERK (Figure 9B), and p-CREB (Figure 9C) expression, whose expressions were decreased with Oxygen glucose deprivation (OGD), while this enhanced effect induced by TMP (Figure 9A, F (1, 20) = 90.590; P < 0.0001; Figure 9B, F (1, 20) = 59.570; P < 0.0001; Figure 9C, F (1, 20) = 38.330; P < 0.0001) was partially counteracted with addition of ANA12, a potent and selective TrkB antagonist (Ding et al, 2020), and/or PD98059, a ERK1/2 signaling inhibitor (Gao et al, 2018) (Figure 9A, F (2, 15) = 8.056; P = 0.0042; Figure 9B, F (2, 15) = 12.550; P = 0.0006; Figure 9C, F (2, 15) = 13.780; P = 0.0004), in primary hippocampal neurons
The underlying mechanism was that TMP facilitated synaptic rehabilitation such as increasing dendritic length, number, and branches, as well as spine density in rats receiving bilateral common carotid arteries occlusion (BCCAO) surgery followed by chronic restraint stress (CRS) for consecutive 14 days, which we named as the rat Behavioral and psychological symptoms of dementia (BPSD) model in the present work (Figure 11)

Summary

Introduction

Dementia is a progressive neurodegenerative disorder causing both functional and cognitive deficits (Cascade et al, 2008; Matthews et al, 2013). The symptoms of BPSD include, but are not limited to, physical aggression, screaming, restlessness, anxiety, depression, apathy, agitation, aberrant motor behavior, sexual disinhibition, hallucinations, delusions, and sleep and appetite disturbances (Pan et al, 2013; Kales et al, 2015; Bessey and Walaszek, 2019) These distractions always result in accelerated cognitive and functional deterioration, declined quality of life, and elevated mortality in sufferers with dementia, which impose higher burdens for caregivers, high risk of institutionalization, and higher costs of care (Finkel, 2001). Derivatives extracted from Chinese herbal medicines might provide a suitable and safe candidate for improving BPSD, as well as avoiding side effects for a long-time treatment using antipsychotics

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