Unlocking the Potential of Trillium Tschonoskii Maxim in Post-Stroke Cognitive Impairment: A Journey Through the Sonic Hedgehog Pathway

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Post-stroke cognitive impairment (PSCI) presents a significant challenge in the realm of neurological disorders, ranging from mild cognitive impairment to stroke-related dementia.

The prevalence of stroke in China is alarmingly high, and PSCI can affect over one-third of stroke patients. This condition not only poses a considerable burden on healthcare resources but also significantly impacts the quality of life for those affected.

In recent years, researchers have turned their attention to traditional Chinese herbs, such as Trillium Tschonoskii Maxim (TTM), as a potential treatment for PSCI.

One of its bioactive components, diosgenin glucoside, shows promise in offering neuroprotection. This article delves into the mechanisms of PSCI, the therapeutic potential of TTM, and the role of the Sonic Hedgehog (Shh) pathway in promoting neurological recovery.

Introduction:

Post-stroke cognitive impairment (PSCI) is a multifaceted cognitive disorder that can result from stroke-related damage. PSCI ranges from mild cognitive impairment to full-blown stroke-related dementia, causing a substantial healthcare burden. In China alone, the prevalence of stroke is high, with an incidence rate of 276.7 per 100,000 and a mortality rate of 153.9 per 100,000.

Shockingly, PSCI can affect over one-third of stroke patients, yet the underlying mechanisms remain enigmatic. PSCI is characterized by chronic progressive cognitive decline, imposing a substantial impact on patients’ lives and healthcare resources.

Trillium Tschonoskii Maxim (TTM): A Potential Solution:

Trillium Tschonoskii Maxim (TTM), a traditional Chinese herb, has been traditionally used to treat traumatic brain injuries and headaches. A bioactive compound in TTM, diosgenin glucoside, has shown neuroprotective properties, although its exact pharmacological mechanisms are not fully understood.

Prior research has demonstrated that total saponins from Trillium Tschonoskii Maxim (TSTT), which includes diosgenin glucoside, can induce autophagy by downregulating miR-155 and activating the Rheb/mTOR signaling pathway, reducing spinal cord injury, and promoting spinal nerve regeneration.

Sequential studies have also revealed that TSTT can induce autophagy, alleviate learning and memory impairment, and exert anti-aging effects. These findings have led to the widespread use of TSTT for ischemic stroke and other neurodegenerative diseases. Nevertheless, the precise neuroprotective mechanisms of TSTT remain elusive.

The Sonic Hedgehog (Shh) Pathway:

The Sonic Hedgehog (Shh) pathway is a complex signaling network crucial for various processes, including embryonic development, stem cell proliferation and differentiation, axon growth, synapse formation, and angiogenesis, all of which are vital for the development of the central nervous system.

The Shh pathway involves Shh ligands, the transmembrane receptors Patched1 (Ptch1) and Smoothened (Smo), and Gli1. When Shh ligands bind to Ptch1, the inhibitory effect of Ptch1 on Smo is relieved, allowing Smo to translocate to primary cilia. This event triggers Gli1 to enter the nucleus, initiating the transcription of downstream genes.

The endogenous Shh signaling pathway is activated in response to various neurological pathologies, such as ischemic stroke, brain trauma, and infection. This activation helps suppress brain tissue damage, promote neurogenesis, and facilitate synaptic remodeling. Importantly, the Shh pathway can enhance neuronal plasticity, improve cell survival, and mitigate cognitive dysfunction, making it a potential target for therapeutic interventions.

The Protective Role of the Shh Pathway:

Studies have revealed that activation of the Shh signaling pathway in animal models of stroke can enhance brain plasticity, reduce apoptosis, promote angiogenesis, and improve synaptic plasticity and synaptic connections. The application of exogenous Shh peptides or Shh pathway agonists has been shown to significantly increase micro-vessel density and neuronal survival rates in the ischemic boundary area, rescuing cognitive impairment.

In the adult hippocampus, Shh signaling receptors Ptch1 and Smo are expressed in neuronal dendrites. Local activation of Smo induces axonal actin-binding protein expression, promoting neuronal axon growth and accelerating their interaction with the dendrites of target neurons, thus enhancing synaptic connections.

TSTT and the Shh Pathway: A Promising Connection:

Given the multifaceted capacity of the Shh signaling pathway in regulating brain function reconstruction, there is a compelling hypothesis that TSTT may play a crucial role in nerve repair in PSCI model rats through the Shh signaling pathway. This potential connection could offer new avenues for research and therapeutic development in the treatment of PSCI.

Discussion

In this study, we have explored the potential of Trillium Tschonoskii Maxim (TSTT) in ameliorating post-stroke cognitive impairment (PSCI) by utilizing a middle cerebral artery occlusion (MCAO) model. Our findings reveal that spatial learning and memory deficits manifest in MCAO rats, attributable to excessive hippocampal neuronal apoptosis and a reduction in synapse-associated proteins. TSTT administration effectively counteracts cognitive dysfunction by inhibiting apoptosis and promoting synaptic remodeling through the activation of the Sonic Hedgehog (Shh) pathway.

The Prevalence and Consequences of PSCI:

PSCI, with a prevalence ranging from 30% to 50%, is a distressing consequence of stroke that often leads to severe impairments in attention and executive functions. Regrettably, conventional medications for PSCI have not shown convincing efficacy. However, there is a growing body of evidence suggesting that traditional Chinese medicine may hold the key to enhancing cognitive function.

In a previous study, we demonstrated that TSTT improved learning and memory capacity in rats with D-galactose-induced brain aging by mitigating hippocampal neuron apoptosis. In this current investigation, the Morris water maze test confirmed that TSTT significantly improves cognitive function in MCAO rats, indicating that it has a promising role in treating acute cerebral ischemia.

TSTT Protects Against Brain Damage in PSCI:

The hippocampus and cerebral cortex are integral components of the brain’s memory network. During ischemic stroke, reduced blood flow results in severe brain injury and excessive accumulation of free radicals, calcium overload, and excitotoxicity. This cascade of events leads to neuronal apoptosis and, consequently, cognitive decline or permanent memory impairment. TSTT treatment was shown to significantly increase neuronal counts and Nissl bodies in the CA1 region of the hippocampus and the cortex penumbra, highlighting its protective effects against brain damage in PSCI rats.

TSTT Enhances Synaptic Plasticity:

A hallmark of PSCI is the reduction in synaptic numbers and connection density due to acute injury. The central nervous system demonstrates significant plasticity following injury, particularly in the context of synaptic plasticity. Our results revealed that TSTT treatment significantly increased dendritic spine density, the number of positive cells, and the expression levels of synaptic markers such as PSD-95, SYN, and GAP-43 in MCAO rats. This suggests that TSTT effectively enhances the synaptic plasticity of hippocampal neurons.

The Role of the Shh Pathway:

The Sonic Hedgehog (Shh) pathway is implicated in various aspects of nervous system development and function, from neurogenesis to synaptic circuit formation. Past studies have highlighted the protective role of the Shh pathway in ischemic stroke, affecting processes such as apoptosis, glutamate excitotoxicity, neuroplasticity, angiogenesis, neurogenesis, and inflammation. In our study, we observed heightened activation of the Shh pathway in response to TSTT treatment, as evidenced by increased expression of synaptic markers PSD-95, SYN, and GAP-43. This suggests that TSTT activates the Shh pathway to promote synaptic remodeling, although the precise regulatory mechanisms warrant further investigation.

TSTT and Apoptosis:

Shh has been demonstrated to inhibit apoptosis in various cell types. Activation of the PI3K/Akt pathway by exogenous Shh peptides has been shown to protect astrocytes from apoptosis. In our study, TSTT treatment significantly downregulated the levels of pro-apoptotic proteins such as Bax and cl-caspase-3 caspase-3 ratios, while upregulating anti-apoptotic Bcl-2. Furthermore, TSTT reduced the number of TUNEL-positive cells in the cerebral cortex of the model rats, indicating that TSTT mitigates apoptosis in a manner reminiscent of Shh peptides. These findings suggest that TSTT restores cognitive function by activating the Shh signaling pathway and attenuating apoptosis.

TSTT and Axonal Remodeling:

Neurons can secrete Shh to promote synaptic remodeling, and astrocytes can also secrete Shh, enhancing synaptic connectivity. We hypothesize that post-stroke neuronal apoptosis results in a loss of Ptch1, activating the Shh pathway in neurons within the ischemic penumbra. This, in turn, triggers the expression of genes related to synaptic remodeling, such as Sparc. TSTT may enhance and amplify Shh signaling, promoting synaptic remodeling. It is worth noting that the Shh pathway may initiate a cascade of signaling pathways mediated by other molecules to activate synaptic remodeling.

Implications and Future Directions:

Recent research has revealed that TSTT interventions can promote brain function recovery through the regulation of axonal remodeling. Further investigation into the precise mechanisms, such as the GSK-3/β-catenin/CRMP-2 pathway, is ongoing. In this study, we have focused on the effects of long-term TSTT interventions on learning and memory function in the chronic phase of ischemic stroke. We have demonstrated that TSTT promotes brain remodeling, possibly mediated by the Shh signaling pathway. This research represents a significant addition to the study of TTM’s potential mechanisms in brain remodeling.

In conclusion, our findings underscore the potential of TSTT in alleviating PSCI by mitigating neuronal apoptosis, enhancing synaptic plasticity, and activating the Shh pathway. This research provides new insights into the treatment of post-stroke cognitive impairment and opens up avenues for further exploration, including the role of TSTT in axonal remodeling and the specific mechanisms underlying its interactions with the Shh signaling pathway.


reference link: https://www.frontiersin.org/articles/10.3389/fphar.2023.1255560/full

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