Vol 59, No 1 (2023)

The lymphatic system not only plays an important role as a drainage eliminating metabolic wastes and toxins from tissues, but also represents an arena for the unfolding of immune response scenarios aimed at protecting the organism from bacteria and viruses. In the central nervous system (CNS), drainage processes proceed with the same intensity as in peripheral tissues. The brain actively exchanges nutrients with the blood and excretes metabolic waste products through the drainage paths closely related to the peripheral lymphatic system. The same routes allow the traffic of immune cells and antibodies to the CNS, thus providing a communication between the peripheral and central immune systems. Over the two-century history of brain drainage studies, a lot of facts have been accumulated to suggest indirectly the presence of lymphatic vessels in the CNS. However, even with the advent of high-tech imaging of brain structures and a rediscovery of the meningeal lymphatic vessels (MLVs), which was a watershed in neuroscience, scientists have not advanced beyond4 confirming the already existing dogma that the lymphatic network is present exclusively in the brain meninges, but not in brain tissues. In fact, however, the rediscovery of MLVs by American scientists was not a “true revelation”, as they were first described by the Italian anatomist Mascagni two centuries earlier, and his results were confirmed later on in many other studies performed on the meninges in humans, macaques, rodents, dogs, rabbits and zebrafish. As a result, the scientific community did not recognize the “forgotten” MLVs as a new discovery. This review highlights the turning points that occurred in neuroscience, when a new player has entered the game and set in order bicentennial efforts of scientists to explain how unnecessary molecules and toxins are removed from the brain, as well as how drainage and immunity are implemented in the CNS. This is an important informational and creative platform both for new fundamental knowledge about the lymphatic system in the brain, as well as for the development of innovative neurorehabilitation technologies based on the management of lymphatic drainage processes.

Intranasal insulin is one of the most promising protectors in the treatment of neurodegenerative and other diseases associated with brain injuries. In these diseases, insulin levels in the brain (in contrast to its blood levels) are as a rule heavily reduced, which, along with the development of insulin resistance, leads to impaired insulin signaling in neurons. The aim of this work was to study the protective effect of insulin on cultured rat cortical neurons using an in vitro oxygen–glucose deprivation (OGD) model of ischemia–reperfusion brain injury followed by a resumption of oxygen and glucose supply to neurons. OGD exposure for 1 or 3 h with subsequent incubation of cultured rat cortical neurons in complete (oxygen- and glucose-containing) growth medium decreased neuronal viability and increased the production of reactive oxygen species, while the preincubation of neurons with insulin at micromolar concentrations had protective and antioxidant effects. One-hour OGD followed by incubation in complete growth medium led to downregulation of protein kinase B/Akt (decreased pAkt(Ser⁴⁷³)/Akt ratio) and upregulation of glycogen synthase kinase-3beta (GSK-3beta), one of the main Akt targets (decreased pGSK-3beta(Ser⁹)/GSK-3beta ratio). In contrast, preincubation with insulin activated Akt and inactivated GSK-3beta. Apparently, these effects of insulin significantly contribute to its neuroprotective action, because GSK-3beta activation leads to mitochondrial dysfunction and neuronal death. Insulin was shown to increase the neuronal activity of protein kinase regulated by extracellular signals (ERK1/2), which was diminished by OGD and subsequent exposure to growth medium containing glucose and oxygen.

The development of approaches to therapy of ischemic brain injuries requires a better insight into the mechanisms that regulate both apoptotic and autophagic death of neurons. Under a strong ischemic (or other pathological) exposure, neurons can die from the activation of both apoptosis and autophagy. This work was aimed to assess the contribution of autophagy and apoptosis activation to neuronal cell death in the hippocampal CA1 region and frontal cortex using the rat two-vessel occlusion/hypotension model of global forebrain ischemia with subsequent long-term reperfusion, as well as to study the ability of intranasal insulin to prevent autophagic and apoptotic death of neurons. The inhibitors of autophagy (3-methyladenine), apoptosis (Ac-DEVD-CHO), or phosphate buffer (for control) were administered to rats intracerebroventricularly before ischemia and reperfusion. To count viable neurons, brain sections were stained with a Nissl stain. During ischemia–reperfusion, the number of viable neurons in the hippocampal CA1 region decreased by 58.3 ± 1.5% of their count in sham-operated rats (control taken as 100%). The administration of autophagy or apoptosis inhibitors increased the number of viable neurons in the hippocampal CA1 region from 58.3 ± 1.5% to 90.4 ± 2.2% (p < 0.001) and 71.6 ± 1.8% (p < 0.001) vs. control, respectively. Intranasal insulin administration at a dose of 0.5 IU (before ischemia and at a daily basis for 7 days during reperfusion) normalized the number of viable neurons in the hippocampal CA1 region up to 100.2 ± 1.95% vs. control. In the frontal cortex, the viability of neurons also decreased under ischemia–reperfusion, while the number of viable neurons increased after the administration of autophagy or apoptosis inhibitors, and even to a greater extent after intranasal insulin administration. The main difference was a lower sensitivity of cortical vs. hippocampal neurons to ischemia–reperfusion. These data indicate that intranasal insulin is able to decrease the death of brain neurons caused by the activation of autophagy and apoptosis due to ischemia–reperfusion.

Multifrequency bioimpedance studies were performed in rats subjected to an eight-week swimming course followed by an eight-week no-exercise period and control animals. A significantly lower ratio of the phase angles of the bioelectrical impedance of the lung tissue at two frequencies of electric current in rats after prolonged physical activity in comparison with control animals was revealed, which may indicate structural and functional changes in the lung tissue. No significant differences were found in the bioimpedance of the myocardium of the left ventricle of the heart in rats of the two groups after eight weeks of swimming. A significantly lower active resistance of the bioelectrical impedance of the myocardial tissue and a significantly higher ratio of the bioelectrical impedance resistance of the lung tissue at two frequencies of electric current in detrained rodents were observed in comparison with the control, which may indicate an excess of intercellular fluid, partial persistence of exercise-induced myocardial angiogenesis after an eight-week of detraining.