The Role of Platelets in the Stimulation of Neuronal Synaptic Plasticity, Electric Activity, and Oxidative Phosphorylation: Possibilities for New Therapy of Neurodegenerative Diseases

Abstract

The central nervous system (CNS) is highly vascularized where neuronal cells are located in proximity to endothelial cells, astroglial limitans, and neuronal processes constituting integrated neurovascular units. In contrast to many other organs, the CNS has a blood-brain barrier (BBB), which becomes compromised due to infection, neuroinflammation, neurodegeneration, traumatic brain injury, and other reasons. BBB disruption is presumably involved in neuronal injury during epilepsy and psychiatric disorders. Therefore, many types of neuropsychological disorders are accompanied by an increase in BBB permeability leading to direct contact of circulating blood cells in the capillaries with neuronal cells in the CNS. The second most abundant type of blood cells are platelets, which come after erythrocytes and outnumber ~100-fold circulating leukocytes. When BBB becomes compromised, platelets swiftly respond to the vascular injury and become engaged in thrombosis and hemostasis. However, more recent studies demonstrated that platelets could also enter CNS parenchyma and directly interact with neuronal cells. Within CNS, platelets become activated by recognizing major brain gangliosides on the surface of astrocytes and neurons and releasing a milieu of pro-inflammatory mediators, neurotrophic factors, and neurotransmitters. Platelet-derived factors directly stimulate neuronal electric and synaptic activity and promote the formation of new synapses and axonal regrowth near the site of damage. Despite such active involvement in response to CNS damage, the role of platelets in neurological disorders was not extensively studied, which will be the focus of this review.

The multifaceted role of platelets in mediating brain function

“… 71 Moreover, direct contact with brain glycolipid structures present in the membranes of astrocytes further activates platelets and stimulates neuroinflammation, 53 leading to immune cell recruitment into the brain parenchyma 74 and the simultaneous release of trophic factors. 27,53,72 Interestingly, this cascade of events creates a microenvironment where proinflammatory cytokines, neurotrophic factors, and neurotransmitters coexist, which, in response to CNS damage, can stimulate new synapse formation and axonal regrowth. 27 A specific role in the modulation of neuroinflammation has been assigned to the α-granule chemoattractants CXCL4 and CCL5 through monocyte recruitment, or MIP-1a (macrophage inflammatory protein-1a) 67,75 because of interaction with immune cells, BBB cellular components, astrocytes and microglia, as well as neurons themselves.…”

“… 27,53,72 Interestingly, this cascade of events creates a microenvironment where proinflammatory cytokines, neurotrophic factors, and neurotransmitters coexist, which, in response to CNS damage, can stimulate new synapse formation and axonal regrowth. 27 A specific role in the modulation of neuroinflammation has been assigned to the α-granule chemoattractants CXCL4 and CCL5 through monocyte recruitment, or MIP-1a (macrophage inflammatory protein-1a) 67,75 because of interaction with immune cells, BBB cellular components, astrocytes and microglia, as well as neurons themselves. Together, these observations highlight the contribution of various platelet factors in neuroinflammation and have provided incentives for preclinical studies where the protective effect of antiplatelet adjunct therapy, such as aspirin, has been examined.…”

A Multidisciplinary Hypothesis about Serotonergic Psychedelics. Is it Possible that a Portion of Brain Serotonin Comes From the Gut?

“…Latest experiments found that platelets can enter the CNS parenchyma and directly interact with neuronal cells [127]. When platelets are activated in the CNS, they release various pro-inflammatory mediators, neurotrophic factors, and neurotransmitters, which stimulate neuronal electrical and synaptic activity and promote the development of new synapses and axonal reconstruction near the site of damage [127].…”

“…Latest experiments found that platelets can enter the CNS parenchyma and directly interact with neuronal cells [127]. When platelets are activated in the CNS, they release various pro-inflammatory mediators, neurotrophic factors, and neurotransmitters, which stimulate neuronal electrical and synaptic activity and promote the development of new synapses and axonal reconstruction near the site of damage [127]. Kopeikina and Ponomarev emphasize [127]: "Platelets and their secreted factors could affect many cell types involved in the regulation of BBB integrity including endothelial cells, astroglia, and pericytes".…”

“…It can be seen that 5-HT could be transported from the bloodstream to the CNS by various proposed mechanisms. Namely, by the help of pEVs [126]; by the help of SERT that is present in the BBB [123]; by means of increased plasma 5-HT level that can increase permeability of microvessel endothelial cells as well as the BBB [118,[128][129][130]; by PAF that modulates the function of the brain microvascular endothelial cells-that are the major component of the BBB-and increases the permeability of the BBB [115,128]; or platelets may enter CNS parenchyma and directly interact with neuronal cells [127].…”