Written by Ben Bunting: BA(Hons), PGCert.
Assisted reproductive therapy (ART) involves the use of drugs and other substances that can affect sperm motility. In order to understand why these drugs work, it is important to know how sperm motility works. This article will discuss some of the major factors that control sperm motility. It will also discuss the various drugs that are used to suppress sperm motility.
PTX inhibits sperm motility
PTX inhibits sperm motility. PTX is a tri-substituted xanthine derivative that binds to PDE4D, PDE10A and PDE11A. PTX is widely used in assisted reproduction to select viable spermatozoa for in vitro fertilization. However, it is reported to have adverse effects on oocyte function and early embryo development. It has also been reported to induce a premature acrosome reaction.
During natural conception, sperm motility is necessary for sperm to reach the site of fertilization. Increased sperm motility is associated with increased sperm survival. Increasing sperm motility improves the outcome of assisted reproductive technology. This article summarizes some recent data on PTX and associated applications in assisted reproduction.
PTX inhibits sperm motility in vitro. It also induces toxic effects on oocyte function and early embryodevelopment. PTX is commonly used for viable sperm selection in asthenozoospermic patients. But there is not sufficient evidence about the safety of ICSI after PTX administration. In the present study, PTX and its analogue PTXm-1 were screened for their effect on sperm motility. It was found that PTXm-1 is more effective than PTX in modulating sperm properties. It also exhibits a lower genotoxic effect on mouse bone marrow cells and human lymphocytes in vitro. It has a higher phosphorylation activity on ERK1/2 compared to PTX.
The analogues were formulated by considering the physico-chemical properties of the binding pocket. The designed compounds had more stable complexes with the PTX. They also displayed a decreased DGbind and a better acrosome reaction compared to PTX.
The binding affinities of these compounds were determined by computational and experimental methods. In this study, the experimental DGbind correlated with the computational DGbind. Moreover, PTX and PTXm-1 had similar beneficial effects at a lower concentration.
Surface molecules regulate motility
Several factors influence sperm motility. Some of these factors are intrinsic and some are extrinsic. Despite the importance of sperm motility for reproductive success, the precise causes of sperm motility deficiencies are not fully understood.
Several experimental studies have been conducted to study the molecular mechanisms involved in sperm motility. One study has identified some of the main deregulated pathways associated with sperm motility dysfunction. These pathways include energetic metabolism, protein folding/degradation and vesicle trafficking.
In another study, the phosphorylation patterns of different proteins were investigated by using two complementary approaches. The first approach involved labeling of the protein with TMT and LC-MS/MS. The second approach involved 2D electrophoresis MALDI-TOF MS. The resultant proteomic profile of asthenozoospermic patients was compared to that of healthy men.
The analysis of protein profiles of asthenozoospermic patients indicated that the most downregulated protein was Chain A, Human Dj-1 with sulfinic acid (DJ-1). The PHGPx, GAPDS and COX6B were also found to be significantly downregulated.
The fibrous sheath plays a critical role in sperm motility. The deletion of the AKAP4 gene leads to dysplasia of the fibrous sheath and a decrease in sperm motility.
Calcium is a key ion in sperm motility signaling. It is primarily used to activate downstream signaling molecules. It acts on a variety of cellular processes to increase the intracellular calcium reservoir, regulate the capacitation of spermatozoa, and activate the opening of CatSper.
Sodium (Na+)-bicarbonate (Na+-HCO3-) co-transporters have been identified as an important downstream effector of the calcium-mediated activation of sAC. Other ions such as hydrogen ion efflux and intracellular pH regulation are also important.
Various pharmacological agents have been used to enhance sperm motility. Verapamil and LY294002 have been used as Ca2+ channel inhibitors and phosphoinositide 3-kinase inhibitors, respectively.
cAMP/protein kinase A
Several biomolecules have been reported to increase sperm motility in vitro and in vivo. Some of the biomolecules are derived from Tribulus terrestris extract, which is rich in antioxidants. Similarly, another biomolecule called forward motility-stimulating factor (FMSF) was found to be active in promoting the transmembrane adenylate cyclase (AC) activity.
Moreover, bicarbonate ions also play a crucial role in regulating sperm motility. These ions contribute to the regulation of pH inside the spermatozoa. Hence, the presence of these ions enhances the cellular level of cAMP. The increase in cAMP levels leads to frequent flagellar beats. Alternatively, it may also activate guanine nucleotide exchange factors.
Other molecules that might regulate sperm motility include reactive oxygen species (ROS), hydrogen ions, and calcium ions. These molecules are produced as by-products of metabolic processes. These molecules are highly reactive and can damage proteins, lipids, and the plasma membrane.
The adenylate cyclase phosphates ATP and then converts it to cAMP. This is essential for normal sperm motility. However, this process is blocked in adenylate cyclase mutants.
During the epididymis, immature sperm undergo biochemical changes that lead to an increase in the cAMP level. In addition, the intracellular pH of the sperm is regulated by the hydrogen ion efflux. This increases the intracellular Ca2+ reservoir and activates the opening of CatSper.
The cAMP-dependent protein kinase is present on the surface of the sperm cell. This kinase is activated by cAMP and initiates flagellar movement. Besides, tyrosine kinase is an important player in regulating forward motility.
Furthermore, incubation of immotile sperm cells with epididymal and seminal plasmas led to an induction of motility. This was supported by the results of stop-motion imaging.
phosphoinositide 3-kinase signalling
Several mechanisms regulate the phosphoinositide 3-kinase signalling in sperm motility. These include the regulation of intracellular pH, the activation of protein kinase A, and the cAMP/protein kinase A pathway. This review discusses these pathways, and highlights how these factors are involved in the regulation of sperm motility. It also describes pharmacological agents and biomolecules that may enhance sperm motility in vitro.
Ca2+ and HCO3- concentrations are key in regulating intracellular sperm pH. They are also important for enhancing sperm motility.
The phosphoinositide 3-kinase pathways involve the interaction of phosphoinositides with receptor tyrosine kinases, and G-proteins. The phosphoinositides then produce moieties involved in the inositol phospholipid signalling pathway. These phosphoinositides are then incorporated into the acrosomal sperm head to promote flagellar movement.
The acrosomal sperm head is a highly polarized membrane that is able to increase its permeability to bicarbonate and calcium ions. It is also destabilized due to the increased efflux of cholesterol. These effects are responsible for the increased polarization of the plasma membrane and membrane fluidity.
Sperms are divided into three main parts: the head, the tail, and the midpiece. Each part is associated with a unique metabolic pathway.
The acrosomal proximal end is enriched in ecto-cAMP-dependent protein kinases. These kinases phosphorylate a range of endogenous proteins. The protein kinase is the most active pathway involved in phosphoinositide 3-kinase signals in sperm motility.
In the cAMP/protein kinase pathway, the catalytic subunit phosphorylates exogenous proteins in the presence of ATP. The protein kinase also interacts with calmodulin, which orchestrates a series of cascades. The cAMP/protein kinase activity is accompanied by the release of inorganic phosphate and the activation of adenylate cyclases.
ROS causes decreased motility
Deficiencies in the antioxidant defense system of spermatozoa are detrimental to their function. The loss of this protection can cause oxidative damage, which can lead to infertility in males.
Oxygen is essential to life. All aerobic organisms, including humans, need it for normal functions. However, when an organism is exposed to pollutants or unhealthy lifestyles, the production of ROS increases. In addition, oxidative stress damages spermatozoa genetic material and impairs their reproductive capacity.
The plasma membrane of spermatozoa contains polyunsaturated fatty acids (PUFA) that are susceptible to lipid peroxidation. This process reduces the integrity of the plasma membrane, which leads to sperm pathology.
High concentrations of ROS alter the fluidity of the plasma membrane, leading to decreased motility and sperm viability. This effect occurs during signal transduction through the epididymis. The enzyme glutathione reductase acts on the sperm membrane to scavenge ROS.
Spermatozoa also have an inherent capacity to generate ROS. These molecules are metabolic intermediates for signal transduction. They affect a number of important cellular mechanisms, including capacitation and acrosome reaction.
Inhibition of oxidative stress by antioxidants improves sperm motility. These compounds include zinc, manganese, and chrome. These substances also act as chelators to prevent inflammation.
In addition to these antioxidants, the cells of the semen have an antioxidant enzyme system. These enzymes, such as superoxide dismutase (SOD), are capable of scavenging ROS. These enzymes are responsible for maintaining the optimal concentrations of extra- and intracellular Ca2+ and HCO3-.
ROS play a crucial role in the regulation of sperm function. In the early stages of sperm development, male germ cells produce a small amount of ROS. This is necessary to allow for functional evolution.
Several factors influence sperm motility. The main swimming characteristic is the lateral movement of the sperm head. This is achieved by an increased membrane fluidity. This increased permeability is also due to a marked efflux of cholesterol. The membrane polarization is also affected by changes in protein phosphorylation.
Some pharmacological agents are used to enhance sperm motility. These include pentoxifylline, which inhibits phosphodiesterase. This agent increases the forward and horizontal movement of sperm. However, it is reported to induce premature acrosome reaction. This is a disadvantage of this treatment. It may also have toxic effects on oocytes.
In addition, it is known that acrosome reaction is critical for capacitation. The biochemical changes that occur during this reaction include a change in plasma membrane polarization, a destabilization of the acrosomal sperm head, and an increase in protein phosphorylation.
Reactive oxygen species (ROS) play an important role in regulating sperm motility. ROS are highly reactive and cause chain reactions that damage proteins and lipids. A low level of ROS is required for normal sperm functioning. But, high levels of ROS are produced by genitourinary tract infections, chronic inflammation, and ageing.
Despite the importance of these factors, there are still uncertainties about their exact role. In this review, we explore the general mechanisms involved in regulating sperm motility and discuss some of the potential applications of pharmacological agents to improve sperm motility in assisted reproduction.
In addition to identifying these potential pathways, we identified a novel protein that promotes sperm motility. This protein was found to be a 66-kDa heat-stable protein distributed on the surface of sperm cells. This protein showed increased forward and horizontal movement and cAMP independent activity.