The medial prefrontal cortex (mPFC) receives dense noradrenergic projections from the locus coeruleus. Adrenergic innervation of mPFC pyramidal neurons plays an essential role in both physiology (control of memory formation, attention, working memory and cognitive behavior) and pathophysiology (attention deficit hyperactivity disorder, posttraumatic stress disorder, cognitive deterioration after traumatic brain injury, behavioral changes related to addiction, Alzheimer’s disease and depression). The aim of this study was to elucidate the mechanism responsible for adrenergic receptor-mediated control of the resting membrane potential in layer V mPFC pyramidal neurons. The membrane potential or holding current of synaptically isolated layer V mPFC pyramidal neurons was recorded in perforated-patch and classical whole-cell configurations in slices from young rats. Application of noradrenaline, a neurotransmitter with affinity for all types of adrenergic receptors, evoked depolarization or inward current in the tested neurons irrespective of whether the recordings were performed in the perforated-patch or classical whole-cell configuration. The effect of noradrenaline depended on β1- and not α1- or α2-adrenergic receptor stimulation. Activation of β1-adrenergic receptors led to an increase in inward Na+ current through HCN channels, which carry a mixed Na+/K+ current. The protein kinase A and C-, glycogen synthase kinase-3β- and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between β1-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the βγ subunit of G protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through β1-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the βγ subunit.

Epilepsy is a neurological disease that affects approximately 1% of the world’s population. Epilepsy is characterized by the occurrence of repeated epileptic seizures due to abnormal neuronal activity. Although this disorder is currently incurable, it can be controlled for years with the appropriate therapy and patient adherence. Inflammation is an organism’s natural response to a pathological stimulus, aimed at eliminating the triggering factor. Multiple studies point out a significant correlation between an increased level of inflammatory mediators and the frequency of epileptic seizures. Increased levels of IL-1β, IL-2, IL-4, IL-6, IFN-γ, and TNF-α were found in the serum of patients with epilepsy. Additionally, pro-inflammatory cytokines were found to be upregulated during epileptic activity in rodents: CCL2 and CCR2 receptor expression was shown to be upregulated during inflammation induced by lipopolysaccharide administration, and CXCR5 was found to be primarily upregulated in brain cells. Early detection of the described factors may serve as a biomarker for epilepsy but also hold potential in developing novel immunomodulating therapies. Thus, a better understanding of the immune system’s involvement is necessary for the development of new therapeutic perspectives in epilepsy.

The aim of our study was to retrospectively assess any correlation between graft fibrosis and selected immunological factors in pediatric liver transplant recipients. The study was performed on 33 patients after living related donor transplantation, divided into 2 groups depending on history of acute rejection episodes after transplantation. We assessed liver biopsies for presence of fibrosis, signs of antibody-mediated rejection, inflammatory infiltrations, and changes in bile ducts. We correlated these findings with assessment of anti-HLA antibodies. Among 14 patients with ACR, a history fibrosis was found in 8 patients (57%). In 19 patients without a history of ACR, fibrosis was found in 9 patients (47%). Anti-HLA antibodies were found in 47% of patients with fibrosis and in only 18.75% of patients without fibrosis. Among 3 patients with signs of antibody-mediated rejection, all had fibrosis in the graft 2 years after transplantation. We did not find any patient with chronic rejection or ductopenia. We suggest that there is a correlation between ACR and development of graft fibrosis present in liver grafts from recipients with normal liver biochemistry. Anti-HLA antibodies class II seems to be most important in development of fibrosis.

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg²⁺), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg²⁺ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg²⁺ (40 mg/kg intraperitoneally). Mg²⁺ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg²⁺ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.

Antibody-mediated rejection (AMR), associated with the presence of C4d deposits, is well-defined in kidney transplantation but much less documented in liver transplantation (LTx). The aim of our study was to retrospectively analyze a group of pediatric liver transplant recipients who experienced episodes of acute rejection in the past, for the signs of AMR and its impact on liver histology. Our study population consisted of 18 patients after living related donor liver transplantation with a history of acute cellular rejection (1-5/patient). In all of them, actual liver function was good at almost 2-year median follow-up after transplantation. We reassessed all liver biopsies taken from these children between 5 days to 5.7 years after transplantation for signs of acute cellular rejection and antibody-mediated rejection. In all patients, anti-HLA antibodies were also assessed at least 2 years after transplantation (2.18-12.27 years, median 6.795 years). There were 27 episodes of acute rejection proved by liver biopsy. Signs of AMR were found in 6 of 18 patients (33.3%). In 5 of these patients, donor-specific (DSA) and non-specific anti-HLA antibodies were also identified. In the group of 12 patients with acute rejection without histochemical signs of AMR, anti-HLA antibodies were found in sera of only 5 of 12 patients after transplantation. Our study shows some correlation between C4d-positive reaction in liver biopsies with acute cellular rejection and presence of anti-HLA antibodies, particularly against HLA class II. We did not find any difference in the late graft function, which could be correlated with the presence of AMR. Further studies on larger groups of patients are necessary.