phenanthrenes and Cognitive-Dysfunction

Alzheimer's disease (AD) is a most common neurodegenerative disease. Sodium Tanshinone IIA Sulfonate (STS) has been reported to ameliorate AD pathology. However, the underlying mechanism is still unclear. In this study, AD transgenic mouse model (APP/PS1) was used to explore the potential mechanism of STS against AD. Morris water maze and Y-maze tests showed that administration of STS improved learning and memory abilities of APP/PS1 mice. STS reduced the levels of reactive oxygen species and malondialdehyde, while improved the activity of superoxide dismutase in both hippocampus and cortex in APP/PS1 mice. STS inhibited the activity of acetylcholinesterase, while improved the activity of choline acetyltransferase in APP/PS1 mice. In addition, STS elevated the protein expressions of neurotrophic factors and synapse-related proteins in both the hippocampus and cortex in APP/PS1 mice. At last, STS improved the protein expressions of glucose transporter 1 (GLUT1) and low-density lipoprotein receptor-related protein 1 (LRP1). These results indicated that the potential mechanism of STS on AD might be related to Aβ transportation function via GLUT1/LRP1 pathway. HIGHLIGHTS: STS improves cognitive impairment of APP/PS1 mice. STS ameliorates the oxidative stress damage and improves the cholinergic system. STS protects against neuronal dysfunction and enhances the synaptic plasticity. STS mediates the Aβ transportation of BMECs.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Glucose Transporter Type 1; Mice; Mice, Transgenic; Neurodegenerative Diseases; Phenanthrenes

White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3β pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 μg·kg

Topics: Animals; Cognitive Dysfunction; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neuroprotective Agents; Phenanthrenes; Structure-Activity Relationship; White Matter

Cerebral ischemia is a major health threat to humankind around the world, and the reperfusion methods may provoke irreversible damages to brain tissues, causing impairment of neurological function. The goal of this study is to investigate the potential neurological protective effect of PJ34, a well-characterized poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor, on cerebral ischemia-reperfusion (I/R)-induced injury of the rat model. The cerebral I/R rats were received (3, 6, or 12 mg/kg) injections of PJ34 or saline at 24 h, 6 h before middle cerebral artery occlusion (MCAO) and 1 h, 24 h, and 48 h after MCAO. All rats were subject to the neurological behavior tests by open field test and Morris water maze test. The expression of pro-inflammatory cytokines, Cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) in cerebral tissues was also determined. Our results demonstrated that the administration of PJ34 dose-dependently ameliorated cerebral I/R-induced injury and improved neurological performance of cerebral I/R rats. We also revealed that PJ34 treatment effectively reduced COX2, iNOS, and pro-inflammatory cytokine levels in the I/R-induced injury tissues. Our finding further supports that inhibition of PARP-1 activity is beneficial for reducing post-I/R-induced brain damage via targeting inflammatory response.

Topics: Animals; Brain; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation Mediators; Ischemic Attack, Transient; Male; Morris Water Maze Test; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Reperfusion Injury

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.

Topics: Animals; Cognitive Dysfunction; Dementia, Vascular; Diterpenes; Epoxy Compounds; Hippocampus; Male; NF-kappa B; Oxidative Stress; Phenanthrenes; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

Topics: Animals; Brain Ischemia; Cognitive Dysfunction; Dendritic Spines; Diterpenes; Hippocampus; Male; Neuronal Plasticity; Phenanthrenes; Rats; Rats, Sprague-Dawley; Spatial Learning

Sodium Tanshinone IIA sulfonate (STS) is a derivative of Tanshinone IIA (Tan IIA). Tan IIA has been reported to possess neuroprotective effects against Alzheimer's disease (AD). However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP-) induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg) and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE) and increased the activity of choline acetyltransferase (ChAT) in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3). STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Hippocampus; Humans; Learning Disabilities; Maze Learning; Mice; Non-Neuronal Cholinergic System; Oxidative Stress; Phenanthrenes; Scopolamine