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

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

doi:10.3389/fnins.2021.646537

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

Front Neurosci. 2021 May 6:15:646537. doi: 10.3389/fnins.2021.646537. eCollection 2021.

Authors

Zihu Tan^{1

2}, Jing Qiu^{1

2}, Yuting Zhang³, Qiong Yang⁴, Xixi Yin³, Jia Li⁵, Guangya Liu⁵, Hengfei Li^{2

6}, Guang Yang^{1

2}

Affiliations

¹ Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China.
² Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, China.
³ Clinical College of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China.
⁴ The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.
⁵ College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine/Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, China.
⁶ Department of Infectious Diseases, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China.

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.

Keywords: TrkB/ERK/CREB signaling pathway; behavioral and psychological symptoms of dementia; chronic restraint stress; neurodegenerative disorders; synaptic remodeling; tetramethylpyrazine.