Modified Gan-Mai-Da-Zao decoction for behavioral and psychological symptoms of dementia: preclinical efficacy and molecular mechanisms

BACKGROUND: The behavioral and psychological symptoms of dementia (BPSD) affect over 90% of dementia patients with no effective therapeutic interventions. The Modified Gan-Mai-Da-Zao Decoction (M-GMDZD) is an innovative formula derived from GMDZD, a classical herbal formula commonly prescribed by Chinese medicine (CM) practitioners for psychiatric conditions. AIM: This study aimed to investigate the anti-BPSD effects such as sedative-hypnotic, anxiolytic, and antidepressant-like actions of M-GMDZD in animal models of BPSD. METHODS: M-GMDZD was subjected to the high-performance liquid chromatography (HPLC) for chemical characterization. To investigate the sedative-hypnotic effect of M-GMDZD, ICR mice were intragastrically administered with M-GMDZD for 14 days, followed by intraperitoneal pentobarbital injections. The pentobarbital-induced sleep test was performed to assess the sleep-improving properties of M-GMDZD in mice, while the monoamine neurotransmitter levels in the pentobarbital-treated mouse brains were measured by ELISA. To evaluate anxiolytic and anti-depressant-like effects of M-GMDZD, the bilateral common carotid arteries occlusion combined with chronic restraint stress (BCCAO/CRS) model in rats was established. After drug treatment for 21 days, rats were subjected to behavioral tests, including open field test (OFT), novel recognition test (NORT), sucrose preference test (SPT), forced swim test (FST), and social interaction test (SIT). The brain tissues from BCCAO/CRS rats were collected for biochemical analysis. RESULTS: M-GMDZD significantly prolonged the pentobarbital-induced sleep duration, increased the cerebral 5-hydroxytryptamine (5-HT) level and decreased the cerebral dopamine (DA) level in the pentobarbital-treated mice, showing promising sedative-hypnotic and sleep-improving effects. Moreover, M-GMDZD treatment markedly alleviated the anxiety-related behavioral impairments, ameliorated depression-like deficits, attenuated recognition memory impairments and improved social interaction in the BCCAO/CRS rats, as assessed by a battery of behavioral tests. The anxiolytic and antidepressant-like effects of M-GMDZD were partly attributed to the neurotrophin-3 (NT-3)-mediated neurotrophic mechanisms. We also found that M-GMDZD alleviated BPSD symptoms in BCCAO/CRS rats by restoring synaptic plasticity via the activation of TrkB/ERK/CREB pathway. CONCLUSIONS: This study has demonstrated for the first time that M-GMDZD exhibits potent anti-BPSD properties, including sedative, anxiolytic, and antidepressant-like effects in preclinical models, highlighting its potential as a promising, multi-target therapeutic intervention for the BPSD management.