The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery

FYI.

The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery 

by

Chenye Qiao

,

Zongjian Liu

^* and

Shuyan Qie

^*

Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China

^*

Authors to whom correspondence should be addressed.

Biomolecules 2023, 13(3), 571; https://doi.org/10.3390/biom13030571

Received: 17 January 2023 / Revised: 23 February 2023 / Accepted: 14 March 2023 / Published: 21 March 2023

(This article belongs to the Special Issue Protection, Plasticity, and Physical Rehabilitation in Ischemic Injury (Volume II))

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Abstract

Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase,(Except that it doesn't exist and should be called the neuronal cascade of death signifying extreme urgency while neuroprotection means nothing to survivors and doctor use that to bamboozle patients; 'We didn't get neuroprotection to work'.  As compared to the statement; 'We failed at stopping the neuronal cascade of death  thus allowing millions to billions of your neurons to die'  

WHICH STATEMENT WILL GET YOUR DOCTORS TO SOLVE STROKE? )

and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration(But your doctor knows nothing on how to make it repeatable on demand.) and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.

Keywords:

stroke; neuroplasticity; microglia; microglial phagocytosis; rehabilitation; neuromodulation

1. Introduction

Stroke is a major cause of death and long-term disability, worldwide. Despite constant incidence and declining mortality rates over the past 20 years, the number of stroke survivors continues to decrease [1,2,3]. They are unable to live independently and are more likely to experience subsequent neurological sequelae [4,5]. Stroke can cause focal and global neurological deficits. Different therapeutic principles are adopted in different periods. In the acute stage of stroke, neuroprotection is the main treatment [6]; reducing cerebral ischemia-reperfusion injury (IRI) is also crucial. In the subacute and chronic stages, functional recovery becomes the primary objective. Neuroplasticity is recognized as the basis of functional restoration and neurological rehabilitation after stroke, including remodeling of dendrites and dendritic spines, axonal sprouting, synapse shaping, and neurogenesis. Spontaneous neuroplasticity begins immediately after stroke, reaches a plateau in three to four weeks, and can be sustained in the chronic phase [7]. Spatiotemporal development profoundly affects the reconstruction of neural circuits and brain networks.

Microglia, the resident immune cells of the central nervous system (CNS), play a key role in brain development, homeostasis maintenance, and the disease response of the CNS through phenotypic polarization, morphological changes, and functional transformation. They participate in a variety of pathophysiological processes in the brain, including the promotion of neuronal survival, induction of programmed cell death, immune monitoring and antigen presentation, inflammation regulation, modulation of synaptic activity, synaptic pruning, remodeling, etc. [8,9,10,11,12].

After stroke, the activation, polarization, and phagocytosis of microglia are crucial for regulating the neuroinflammatory microenvironment and enhancing neuroplasticity. Our previous study presented that the development of neuroplasticity overlaps both temporally and spatially with microglial activation [7], suggesting that microglia may have a profound impact on neuroplasticity following stroke and that they may be key therapeutic targets for stroke rehabilitation. In this review, we explore therapeutic targeting at different stages after stroke and the impact of neuroplasticity during this process. We then discuss the functions and mechanisms of microglial activation, polarization, and phagocytosis under physiological and pathological conditions. Finally, we provide a summary of microglia-targeted therapeutic interventions for promoting stroke recovery.

2. Pathophysiology and Therapeutic Target of Stroke Recovery

2.1. Pathophysiology of Stroke in Different Phases

Stroke commonly comprises two pathological subtypes. Hemorrhagic stroke accounts for approximately 10–15% of stroke cases. During this process, stress in the brain and internal injury cause the rupture of blood vessel [13]. Hematomas compressing brain tissue form for blood leakage into the brain parenchyma. The mass effect of the hematoma combined with neurotoxic effects further causes increased intracranial pressure, cerebral herniation, or death [14,15].

Ischemic stroke is caused by abrupt occlusion of the cerebral artery. The consequent interruption of blood flow and obstruction of the supply of oxygen lead to glutamate excitotoxicity, calcium overload, oxidative and nitrosative stress, and the release of inflammatory mediators, thereby activating a series of detrimental signaling cascades that induce neuronal injury or death [1,2,16,17]. Reversible neuronal impairment occurs after an ischemic attack, leading not only to relevant symptoms but also functional deficits corresponding to the location of the ischemia [18]. The progression of brain damage involves irreversibly injured necrotic tissue in the ischemic core, followed by injury development in the penumbral area, and then expanding to the entire ischemic territory [1,19]. Due to focal and global brain neurological damage following stroke, patients have different degrees of neurological deficits after stroke, such as dyskinesia, sensory dysfunction, swallowing dysfunction, dysarthria, aphasia, cognitive impairment, impaired cardiopulmonary function, mental disorders, and many complications, which further leads to a decline in quality of life and social participation [3,20].

Aside from revascularization therapy(thrombolysis and thrombectomy) and neuroprotective therapies (non-pharmaceutical and pharmaceutical therapies) for managing stroke in different phases [21], rehabilitative therapy helps to alleviate disability by promoting the recovery of impairment, activity, or participation after stroke [22] and is formally associated with a “time frame”, which coincides with the development of stroke and the period of maximal spontaneous recovery [23]. Thus, although rehabilitation plays a key role after stroke, not all stages are suitable for rehabilitative interventions [24]. According to both animal models and human trials, intensive rehabilitation within 24 h is potentially harmful [23]. In a clinical trial, a four-week intervention of physical fitness training did not result in an improvement in activities during the subacute period (days 5–45 after stroke) [25].

The therapeutic targets of stroke recovery vary according to the developmental pathophysiological process (Table 1). In the acute phase (minutes to days), a series of detrimental events occur after acute ischemic injury, including infiltration of peripheral immune cells, activation of resident glial cells, disturbance of ionic homeostasis, oxidative stress, mitochondrial dysfunction, and DNA damage. These processes involve cell necrosis within the lesion core and peri-infarct area. Therapeutic strategies have focused on neuroprotection to prevent neuronal injury and death, reduce infarct volume, and limit the decrease in neuronal density in the penumbra [16,26,27,28,29,30,31]. In addition, reducing IRI is critical. During the restoration of blood perfusion, IRI can lead to cerebral edema and even hemorrhage, thereby exacerbating the detrimental biological cascade response and causing irreversible tissue damage [21,32]. Therefore, besides neuroprotection, effective reduction of IRI is also a key target in the treatment of the acute phase of ischemic stroke [33].

Table 1. Pathophysiology and therapeutic targets of ischemic stroke in the acute, subacute, and chronic phases. BBB, blood-brain barrier; ROS, reactive oxygen species.

In the subacute phase (days to weeks), the mechanisms are more complicated than in the acute phase and include amplification of local and systemic immune responses, increased cytokine and reactive oxygen species (ROS) production, cell edema, and ion imbalances [28,34]. The activation of several protective mechanisms triggers beneficial repair processes, including neurogenesis and angiogenesis [27]. In addition, many endogenous processes are active, including axonal sprouting, dendrite remodeling, increased levels of growth factors, and altered synaptic and cortical excitability. Some of these processes have been demonstrated to mediate behavioral changes [35].

In the chronic phase (weeks to months), the end of spontaneous structural recovery is marked by stabilization of the post-stroke neurological deficits [35]. The therapeutic priorities should shift from neuroprotection to functional rehabilitation. Post-ischemic inflammatory responses appear to exacerbate tissue damage at an early stage, whereas they are assumed to promote tissue repair and functional restoration during the chronic phase [36]. During this stage, excitotoxicity decreases and the brain milieu becomes primarily inhibitory, and neural repair and excitability enhancement come to the forefront of post-stroke intervention [22,35].

 

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