mTOR pathway – a potential therapeutic target in stroke

Somebody should take responsibility for creating protocols using rapamycin and hamartin.

. But nothing will occur, there is NO leadership in stroke and NO strategy to solve stroke. You're screwed along with your children and grandchildren when they have strokes. 

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mTOR pathway – a potential therapeutic target in stroke

Konstantinos Melanis https://orcid.org/0000-0002-3224-3053 melaniskos@gmail.com, Maria-Ioanna Stefanou https://orcid.org/0000-0002-2305-6627, […], and Themistoklis Papasilekas+1View all authors and affiliations

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https://doi.org/10.1177/17562864231187770

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• • Abstract
  • Introduction
  • Stroke pathophysiology and the role of autophagy and inflammation
  • The mTOR pathway
  • mTOR and stroke
  • Targeting the mTOR pathway in stroke
  • TSC complex and stroke
  • Conclusion
  • Acknowledgments
  • ORCID iDs
  • Footnotes
  • References
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Abstract

Stroke is ranked as the second leading cause of death worldwide and a major cause of long-term disability. A potential therapeutic target that could offer favorable outcomes in stroke is the mammalian target of rapamycin (mTOR) pathway. mTOR is a serine/threonine kinase that composes two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is regulated by other proteins such as the tuberous sclerosis complex. Through a significant number of signaling pathways, the mTOR pathway can modulate the processes of post-ischemic inflammation and autophagy, both of which play an integral part in the pathophysiological cascade of stroke. Promoting or inhibiting such processes under ischemic conditions can lead to apoptosis or instead sustained viability of neurons. The purpose of this review is to examine the pathophysiological role of mTOR in acute ischemic stroke, while highlighting promising neuroprotective agents such as hamartin for therapeutic modulation of this pathway. The therapeutic potential of mTOR is also discussed, with emphasis on implicated molecules and pathway steps that warrant further elucidation in order for their neuroprotective properties to be efficiently tested in future clinical trials.

Introduction

Ischemic stroke is a severely debilitating and life-threatening neurological disorder characterized by disturbed cerebral blood supply that results into cerebral hypoperfusion and – ultimately – neuronal cell death. Worldwide it is ranked as the second leading cause of death and a major cause of long-term disability.^1,2 Stroke is categorized in two main types, ischemic and hemorrhagic.³ Because of the wide variety of acute ischemic stroke (AIS) causes, several classification schemes have been proposed based on the underlying etiology, including the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification system, that distinguishes between five different AIS types: cardioembolic, thromboembolic, lacunar, cryptogenic, and AIS due to other causes.⁴

The mainstay treatment for ischemic stroke consists today of intravenous thrombolysis and endovascular thrombectomy, both aiming at recanalization of the occluded vessel and reperfusion of the ischemic cerebral tissue.^5,6 The secondary purpose of acute stroke treatments is to mobilize any agents which can alleviate the damage which has already been inflicted upon the nervous tissue. Despite tremendous advances in the field of stroke therapies, time to reperfusion remains the main limiting factor. With this in mind, neuroprotective agents that will attenuate neuronal damage until vessel recanalization may be achieved while also preventing a potential reperfusion injury have recently come into the focus of stroke research. An attractive target for such agents seems to be the mammalian target of rapamycin (mTOR) pathway, which is involved in both autophagy-related apoptosis and inflammation, processes of equally great importance in stroke pathophysiology.

Stroke pathophysiology and the role of autophagy and inflammation

To gain insight into the pathophysiological importance of the mTOR pathway in stroke, the complex pathophysiological processes implicated in cerebral ischemia must first be elucidated.

The chain of events leading to neuronal cell death in ischemic stroke starts with a decrease in cerebral blood flow within a certain area of the brain. This propagates a cascade of cellular and molecular events, known as the ischemic cascade.⁷ During the initial stages of ischemia, glucose- and oxygen-deprived neurons are forced into anaerobic metabolism. This, being an inherently less efficient energy production mode, results into a significant decrease in adenosine triphosphate (ATP) production, while at the same time, triggers release of lactic acid as a byproduct.⁶ Subsequently, ATP-dependent ion transport pumps fail, causing the cell membranes to become depolarized and leading to a large influx of Ca⁺². Intracellular Ca⁺² levels are further increased through the release of glutamate, an excitatory neurotransmitter that binds to and opens Ca⁺²-permeable N-methyl-D-aspartate receptors.⁸ The result of these cascades is activation of lytic enzymes and formation of free radicals.⁹ In this context, of great importance is the role of calpain, a calcium-activated cytosolic protease which cleaves a number of different cytoplasmic and nuclear substrates.¹⁰ Cells affected by ischemia eventually lose their structural integrity with their membranes becoming permeable to all sorts of ions and toxic chemicals and their organelles rendered inoperative. The end result of ischemia is activation of apoptosis and cellular death. Of note, autophagy and inflammation are mechanisms with a prominent role throughout this process. Triggered initially as processes for clearance of necrotic cells and toxic debris, they soon become somewhat of a ‘liability’ propagating brain injury.

Autophagy is a lysosome-mediated process that aims to remove, when activated, misfolded or aggregated cytosolic contents such as those encountered in stroke-affected cells.^11,12 Three types of autophagy are described in the literature, microautophagy, chaperone-mediated autophagy and macroautophagy.¹³ Macroautophagy utilizes double membrane vacuoles called phagophores to transport degraded cytoplasmic material to lysosomes in a five-step process.¹³ First, phagophores engulf their target molecules in a process known as enucleation. Subsequently, this turns them into autophagosomes, organelles that will ultimately merge with lysosomes creating autolysosomes.¹⁴ Autophagosomes have been identified in the hippocampus and also in the penumbra of stroke test animals and their importance in stroke pathophysiology has been well-documented.¹⁵ In particular, the formation of autophagosomes is induced by upregulation of microtubule-associated protein 1 light chain (LC3)-II (Figure 1). Two different forms of LC3 exist (Figure 1). The cytosolic type of LC3 (LC3-I) is conjugated to phosphatidylethanolamine and forms LC3-phosphatidylethanolamine conjugate (LC3-II), which is responsible for the development of autophagosomal membrane¹⁶ (Figure 1). In turn, within autolysosomes, enucleated macromolecules are eliminated through enzymatic cleavage. In the next phases which follow, elongation and expansion of the phagophore take place. Finally, through the transport of proteins to the lysosome the maturation of phagosome is achieved.^17,18 This whole process is regulated through sophisticated signaling pathways, namely those of mTOR and adenosine-monophosphate activated protein kinase (AMPK)^19,20 (Figure 1). mTOR inhibits autophagy by phosphorylating Unc-51-like kinase (ULK)²¹ (Figure 1). AMPK on the other hand promotes autophagy by suppressing mTOR while also directly activating ULK to induce it.²² It should be noted that ischemia propagates autophagy through AMPK activation^23,24 (Figure 1).

Figure 1. Regulation of the autophagic process.

In the autophagic process, mammalian target of rapamycin complex 1 (mTORC1) and adenosine-monophosphate activated protein kinase (AMPK) have an opposing effect. By phosphorylating the Unc-51-like kinase (ULK) complex, AMPK promotes autophagy whereas mTORC1 blocks it. ULK complex is the first step for the initiation of autophagy and an integral part for the development of preautophagosome. The next step for membrane nucleation is the mobilization the transmembrane complex, beclin-1. Autophagy-related genes 4,7,3 (Atg4, Atg7, Atg3) are responsible for the conversion of light chain 3 (LC3) into LC3-II which is important for the development of autophagosome. The double blue structure represents the cell membrane. Black arrows correspond to blocking of activity and red ones correspond to induction. ‘P’ corresponds to phosphorylation.

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