A Novel Case of a Massive Amebic Liver Abscess in the Setting of Uncontrolled Diabetes Mellitus and Concurrent Pulmonary Embolism.

Amebic liver abscesses (ALAs), one of the most common extraintestinal manifestations of invasive amebiasis, pose diagnostic challenges due to their various clinical presentations and difficulty in distinguishing them from pyogenic abscesses. This case presentation highlights the intricacy of determining the source of an unusually large liver abscess that had an even rare occurrence of a coinciding pulmonary embolus without any evidence of a deep vein thrombosis. This unusual combination underscores the challenges in identifying and managing atypical cases of ALA and emphasizes the need for more comprehensive data to enhance our understanding of such occurrences.

Intranasal administration of antiseizure medications in chronic and emergency treatment: Hopes and challenges.

Despite the availability of many antiseizure medications (ASMs), 30 % of patients experience pharmacoresistant seizures. High-throughput screening methods undoubtedly remain one of the most important approaches for discovering new molecules to treat seizures. However, the costly and time-consuming nature of drug development prompts us to explore alternative strategies to counteract drug-resistant seizures. One such approach is to consider intranasal administration of known molecules for seizure treatment. In the case of treating epileptic seizures, administering ASMs intranasally may enhance treatment effectiveness and minimize adverse effects. A good example of changes in drug administration is the intranasal administration of fentanyl, which has become a clinical standard in the emergency setting to treat moderate to severe pain in adults and children. This review discusses the utilization of intranasally administered ASMs for both acute and chronic seizures. It addresses various targeted pharmacokinetic approaches, challenges and prospects associated with these regimens. Brief neuroanatomical and molecular rationale for nose-to-brain drug transport is also presented. Furthermore, recent preclinical studies validating the efficacy and brain distribution following intranasal administration of the most commonly used drugs in chronic treatment are also discussed.

APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation.

INTRODUCTION: We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS: We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions. RESULTS: We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Targeting CD20 in multiple sclerosis - review of current treatment strategies.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) that mostly manifests as irreversible disability. The aetiopathogenesis of MS is still unclear, although it was initially thought to be primarily mediated by T-cells. Research into the immune concepts of MS pathophysiology in recent years has led to a shift in the understanding of its origin i.e. from a T-cell-mediated to a B-cell-mediated molecular background. Thus, the use of B-cell-selective therapies, such as anti- -CD20 antibody therapy, as expanded therapeutic options for MS is now strongly supported. This review provides an up-to-date discussion on the use of anti-CD20 targeted therapy in MS treatment. We present a rationale for its use and summarise the results of the main clinical trials showing the efficacy and safety of rituximab, ocrelizumab, ofatumumab, and ublituximab. Future directions that show selectivity to a broader population of lymphocytes, such as the use of anti-CD19 targeted antibodies, as well as the concept of extended interval dosing (EID) of anti-CD20 drugs, are also discussed in this review.

miR-9a-5p expression is decreased in the hippocampus of rats resistant to lamotrigine: A behavioural, molecular and bioinformatics assessment.

The major obstacle in developing new treatment strategies for refractory epilepsy is the complexity and poor understanding of its mechanisms. Utilizing the model of lamotrigine-resistant seizures, we evaluated whether changes in the expression of sodium channel subunits are responsible for the diminished responsiveness to lamotrigine (LTG) and if miRNAs, may also be associated. Male rats were administered LTG (5 mg/kg) before each stimulation during kindling acquisition. Challenge stimulation following LTG exposure (30 mg/kg) was performed to confirm resistance in fully kindled rats. RT-PCR was used to measure the mRNA levels of sodium channel subunits (SCN1A, SCN2A, and SCN3A) and miRNAs (miR-155-5p, miR-30b-5p, miR-137-3p, miR-342-5p, miR-301a-3p, miR-212-3p, miR-9a-5p, and miR-133a-3p). Western blot analysis was utilized to measure Nav1.2 protein, and bioinformatics tools were used to perform target prediction and enrichment analysis for miR-9a-5p, the only affected miRNA according to the responsiveness to LTG. Amygdala kindling seizures downregulated Nav1.2, miR-137-3p, miR-342-5p, miR-155-5p, and miR-9a-5p as well as upregulated miR-212-3p. miR-9a-5p was the only molecule decreased in rats resistant to LTG. The bioinformatic assessment and disease enrichment analysis revealed that miR-9a-5p targets expressed with high confidence in the hippocampus are the most significantly associated with epilepsy. Due to the miR-9a-5p dysregulation, major pathways affected are neurotrophic processes, neurotransmission, inflammatory response, cell proliferation and apoptosis. Interaction network analysis identified LTG target SCN2A as interacting with highest number of genes regulated by miR-9-5p. Further studies are needed to propose specific genes and miRNAs responsible for diminished responsiveness to LTG. miR-9a-5p targets, like KCNA4, KCNA2, CACNB2, SCN4B, KCNC1, should receive special attention in them.

mTOR and HDAC2 are simultaneously activated during electrically induced kindling of seizures.

Although neurotrophic pathways and epigenetic processes are believed to be significant contributors to epileptogenesis and epilepsy, therapies using modulators of these targets are still lacking. BDNF-TrkB-mTOR signalling and the REST/NRSF-coREST-HDAC2 system are critical pathways responsible for neurotrophic and epigenetic processes, respectively. In our study, we assessed whether these two pathways are activated in a kindling model of seizures. We assessed the protein and mRNA levels of BDNF, TrkB, mTOR, REST/NRSF, coREST and HDAC2 in the brain. The study results showed increased expression of BDNF and decreased coREST in rats subjected to electrical kindling compared to control animals. We also revealed increased expression of both mTOR and HDAC2 in the brain tissue of electrically stimulated animals. mRNA production did not follow the intensified mTOR and HDAC2 protein synthesis. Furthermore, increased expression of BDNF, mTOR and HDAC2 was observed in animals that did not fulfil the kindling criteria in comparison to fully kindled rats. In conclusion, our results suggest that during epileptogenesis, the BDNF/mTOR neurotrophic pathway is mainly activated, with TrkB playing a less important role. Furthermore, the epigenetic transcription factor REST/NRSF was not found to be critical for HDAC2 activation. The simultaneous activation of both mTOR and HDAC2 systems during epileptogenesis confirms multifactorial neuronal adaptation, including neurotrophic and epigenetic processes. Our results may indicate that similar to cancer studies, the coadministration of regulators of both system should be considered a new potential strategy for preventing epileptogenesis.

Increased Hippocampal Afterdischarge Threshold in Ketogenic Diet is Accompanied by Enhanced Kynurenine Pathway Activity.

The efficacy of a ketogenic diet (KD) in controlling seizure has been shown in many experimental and clinical studies, however, its mechanism of action still needs further clarification. The major goal of the present study was to investigate the influence of the commercially available KD and caloric restriction (CR) on the hippocampal afterdischarge (AD) threshold in rats, and concomitant biochemical changes, specifically concerning the kynurenine pathway, in plasma and the hippocampus. As expected, the rats on the KD showed higher AD threshold accompanied by increased plasma ß-hydroxybutyrate level compared to the control group and the CR rats. This group presented also lowered tryptophan and elevated kynurenic acid levels in plasma with similar changes in the hippocampus. Moreover, the KD rats showed decreased levels of branched chain amino acids (BCAA) and aromatic amino acids (AAA) in plasma and the hippocampus. No regular biochemical changes were observed in the CR group. Our results are analogous to those detected after single administrations of fatty acids and valproic acid in our previous studies, specifically to an increase in the kynurenine pathway activity and changes in peripheral and central BCAA and AAA levels. This suggests that the anticonvulsant effect of the KD may be at least partially associated with those observed biochemical alternations.

Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators.

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.

Pro-inflammatory cytokines, but not brain- and extracellular matrix-derived proteins, are increased in the plasma following electrically induced kindling of seizures.

BACKGROUND: The aim of the study was to evaluate the brain-derived proteins, extracellular matrix-derived protein and cytokines as potential peripheral biomarkers of different susceptibility to seizure development in an animal model of epilepsy evoked by chronic focal electrical stimulation of the brain. METHODS: The plasma levels of IL-1ß (interleukin 1ß), IL-6 (interleukin 6), UCH-L1 (ubiquitin C-terminal hydrolase 1), MMP-9 (matrix metalloproteinase 9), and GFAP (glial fibrillary acidic protein) were assessed. The peripheral concentrations of the selected proteins were analyzed according to the status of kindling and seizure severity parameters. In our study, increased concentrations of plasma IL-1ß and IL-6 were observed in rats subjected to hippocampal kindling compared to sham-operated rats. RESULTS: Animals that developed tonic-clonic seizures after the last stimulation had higher plasma concentrations of IL-1ß and IL-6 than sham-operated rats and rats that did not develop seizure. Elevated levels of IL-1ß and IL-6 were observed in rats that presented more severe seizures after the last five stimulations compared to sham-operated animals. A correlation between plasma IL-1ß and IL-6 concentrations was also found. On the other hand, the plasma levels of the brain-derived proteins UCH-L1, MMP-9, and GFAP were unaffected by kindling status and seizure severity parameters. CONCLUSIONS: The plasma concentrations of IL-1ß and IL-6 may have potential utility as peripheral biomarkers of immune system activation in the course of epilepsy and translational potential for future clinical use. Surprisingly, markers of cell and nerve ending damage (GFAP, UCH-L1 and MMP-9) may have limited utility.

Transcriptional Dysregulation in Huntington's Disease: The Role in Pathogenesis and Potency for Pharmacological Targeting.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF- κB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

Topical delivery of a small molecule RUNX1 transcription factor inhibitor for the treatment of proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment surgery failure. Despite significant advances in vitreoretinal surgery, it still remains without an effective prophylactic or therapeutic medical treatment. After ocular injury or retinal detachment, misplaced retinal cells undergo epithelial to mesenchymal transition (EMT) to form contractile membranes within the eye. We identified Runt-related transcription factor 1 (RUNX1) as a gene highly expressed in surgically-removed human PVR specimens. RUNX1 upregulation was a hallmark of EMT in primary cultures derived from human PVR membranes (C-PVR). The inhibition of RUNX1 reduced proliferation of human C-PVR cells in vitro, and curbed growth of freshly isolated human PVR membranes in an explant assay. We formulated Ro5-3335, a lipophilic small molecule RUNX1 inhibitor, into a nanoemulsion that when administered topically curbed the progression of disease in a novel rabbit model of mild PVR developed using C-PVR cells. Mass spectrometry analysis detected 2.67 ng/mL of Ro5-3335 within the vitreous cavity after treatment. This work shows a critical role for RUNX1 in PVR and supports the feasibility of targeting RUNX1 within the eye for the treatment of an EMT-mediated condition using a topical ophthalmic agent.

Individual susceptibility or resistance to posttraumatic stress disorder-like behaviours.

The aim of this study was to explore the neurobiological background of individual susceptibility and resistance to the development of posttraumatic stress disorder (PTSD)-like behaviours. Rats were divided into susceptible, PTSD(+), and resistant, PTSD(-), groups based on freezing duration during exposure to aversive context and the time spent in the central area in open field test one week after threefold stress experience (modified single prolonged stress). PTSD(-) rats showed increased concentrations of corticosterone in plasma and changes in GAD67 expression: decreased in the infralimbic cortex (IL) and increased in the lateral amygdala (LA), dentate gyrus (DG), and CA1 area of the hippocampus. Moreover, in this group, we found an increase in the number of CRF-positive nuclei in the parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN). The PTSD(+) group, compared to PTSD(-) rats, had decreased concentrations of corticosterone in plasma and reduced CRF expression in the pPVN, higher CRF expression in the CA1, increased expression of CRF-positive nuclei and GR receptors in the CA3 area of the hippocampus, and increased expression of GR receptors in the DG and the central amygdala (CeA). Biochemical analysis showed higher concentrations of noradrenaline, glutamic acid in the dorsal hippocampus and amygdala and lower levels of dopamine and its metabolites in the amygdala of the PTSD(+) group than in the PTSD(-) group. The study revealed different behavioural and biochemical profiles of PTSD(+) and PTSD(-) rats and suggested that individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity may determine hippocampal- and amygdala-dependent memory and fear processing.

The role of REST/NRSF, TrkB and BDNF in neurobiological mechanisms of different susceptibility to seizure in a PTZ model of epilepsy.

Global transcriptional disturbances are believed to play a major role in the course of epilepsy. Due to the high complexity, the neurobiological mechanisms underlying different susceptibility to seizure and epilepsy are not well known. A transcription factor called REST/NRSF (repressor element 1-silencing transcription factor/neuron-restrictive silencer factor) is believed to contribute to processes associated with seizure development. Its downstream genes, those encoding BDNF (brain-derived neurotrophic factor) and TrkB (BDNF receptor; tropomyosin receptor kinase B), are also thought to play a role. To verify this hypothesis, we used a PTZ kindling model of epilepsy and divided animals into groups according to their different susceptibility to seizure. The concentrations of REST/NRSF, BDNF, and TrkB protein and mRNA were measured in hippocampal homogenates. The level of REST/NRSF protein measured 24 h after the last PTZ injection was increased in animals resistant to kindling and was unchanged in groups of rats kindled after 5, 10 and 20 in.ections of PTZ. In contrast, TrkB protein concentration was enhanced in all kindled rats and was unchanged in the resistant rats. There were no changes in the protein concentration of BDNF in rats with different susceptibility to kindling; however, data from the combined kindled groups vs. the resistant group revealed an increased level of BDNF in resistant animals. In sum, the increased level of protein REST/NRSF in resistant animals may reflect its neuroprotective role against seizure development. The increased concentration of TrkB protein in kindled animals indicates its pivotal role in the process of epileptogenesis. We propose that in resistant rats, REST/NRSF could contribute to the prevention of TrkB activation related to seizures.

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

The role of UCH-L1, MMP-9, and GFAP as peripheral markers of different susceptibility to seizure development in a preclinical model of epilepsy.

In our study, we assessed the potency of the brain-derived proteins ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), matrix metalloproteinase 9 (MMP-9), glial fibrillary acidic protein (GFAP) and the immune activation indicators interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) as peripheral biomarkers of different susceptibilities to kindling in a preclinical model. We observed increased plasma UCH-L1 levels in kindled vs. control animals. Furthermore, MMP-9 and IL-1ß concentrations were the lowest in rats resistant to kindling. In summary, UCH-L1 is an indicator of neuronal loss and BBB disruption after seizure. MMP-9 and IL-1ß may indicate resistance to kindling. UCH-L1, MMP-9 and IL-1ß may have utility as peripheral biomarkers with translational potency in the clinic.

Epigenetic mechanisms of stress and depression. / Mechanizmy epigenetyczne stresu i depresji.

The etiopathogenesis of mood disorders is not fully understood. Among different possible causes, the involvement of genetic factors is taken into account. The manifestation of clinical symptoms cannot be assigned to a single gene mutation, thus the epigenetic association in the origin of those illnesses is suggested. The epigenetic regulation of gene expression, evoked by environmental stimuli rests upon producing persistent changes in its expression. There are several epigenetic mechanisms that change the accessibility of DNA to transcriptional factors such as acetylation/deacetylation and methylation/demethylation of the histones or an introduction of methyl groups to the cytosine of the DNA. Early and adult stress exposure is believed to have an association with epigenetic alteration of genes involved in mood regulation, for example, genes involved in the regulation of the HPA axis activity (NR3C1) or responsible for the serotonergic neurotransmission (SLC6A4). The data coming from epigenetic research indicate that mechanism of action of some antidepressants such as fluoxetine and escitalopram or mood stabilizers such as valproicacid, is at least partly associated with the epigenetic processes. Moreover, the epigenetic changes in some genes are believed to be promising diagnostic tools. These changes may help to identify the groups of patients particularly vulnerable to mental disorders and may have potential utility as biomarkers facilitating diagnosis and treatment of psychiatric disorders. Taken together, the epigenetic research will reveal neurobiological underpinnings of affective disorders and may open a new pharmacological avenue for patients suffering from mood disorders and other mental disorders.

Looking for novel, brain-derived, peripheral biomarkers of neurological disorders.

The role of blood brain barrier (BBB) is to preserve a precisely regulated environment for proper neuronal signaling. In many of the central nervous system (CNS) pathologies, the function of BBB is altered. Thus, there is a necessity to evaluate a fast, noninvasive and reliable method for monitoring of BBB condition. It seems that revealing the peripheral diagnostic biomarker whose release pattern (concentration, dynamics) will be correlated with clinical symptoms of neurological disorders offers significant hope. It could help with faster diagnosis and efficient treatment monitoring. In this review we summarize the recent data concerning exploration of potential new serum biomarkers appearing in the peripheral circulation following BBB disintegration, with an emphasis on epilepsy, traumatic brain injury (TBI) and stroke. We consider the application of well-known proteins (S100ß and GFAP) as serum indicators in the light of recently obtained results. Furthermore, the utility of molecules like MMP-9, UCHL-1, neurofilaments, BDNF, and miRNA, which are newly recognized as a potential serum biomarkers, will also be discussed.

Altered expression of GABA-A receptor subunits in the hippocampus of PTZ-kindled rats.

BACKGROUND: Changes in the expression of the GABA-A receptor subunits involved in phasic and tonic inhibition have been studied in a wide spectrum of animal models of epilepsy. However, there is no exhaustive data regarding the pentylenetetrazole (PTZ) kindling model of epilepsy. METHODS: The aim of our study was to analyse the hippocampal changes in the expression of GABA-A receptor subunits involved in phasic (α1, γ2) or tonic (α4 and δ) inhibition in rats subjected to the PTZ kindling using immunohistochemistry method as well as in animals subjected to a single injection of a subconvulsive (30mg/kg) or convulsive (55mg/kg) dose of PTZ. Moreover, the expression of GABA transporters (GAT-1 and GAT-3) was also assessed. RESULTS: In kindled animals, we observed an increase in the expression of α1 (in CA1, DG (dentate gyrus) and CA3 regions) and γ2 (CA1 and CA3) subunits as well as in the expression of GAT-1 (CA1). On the other hand, the expression of the δ subunit in the DG was reduced. The single injection of PTZ at a dose of 30mg/kg increased the expression of the α4 subunit in the DG, while at a dose of 55mg/kg, PTZ increased the expression of the α1 and α4 subunits in the DG and reduced expression of the γ2 subunit in the CA1 and CA3 regions. CONCLUSIONS: The pattern of changes observed in our study indicates that changes in tonic inhibition are involved in abnormal neuronal activity observed in PTZ model of epilepsy.

Expression of kisspeptin protein in hypothalamus and LH profile of growing female lambs.

Kisspeptin (kp) is considered to be one of the major regulators of the induction of pubertal events via the activation of the gonadotrophin-releasing hormone-LH system. The aim of the present study was to analyse expression of immunoreactive (ir) kp in the hypothalamic neurons of female lambs from the neonatal to the peripubertal period (5 days to 32 weeks) in relation to the plasma LH pattern using immunohistochemistry and image analysis. Hypothalami were collected from female lambs (n=33) from the infantile, juvenile, prepubertal and peripubertal periods. The population of kp-ir perikarya was detected mainly in the arcuate nucleus and their number increased gradually from 5 to 16 weeks of age and was maintained at a high level up to the peripubertal stage. This was reflected by the significant (P<0.05) gradual increase in the percentage of hypothalamic area occupied by kp-ir neurons and increase in the number of kp-ir perikarya within the arcuate nucleus. The same pattern of kp immunoreactivity was observed in the median eminence. Plasma LH concentration increased from Week 5 to Weeks 12-16 and further increased at Week 32. LH pulse frequency increased from Week 5 to 32 (P<0.05). Thus, changes in kp expression reflected changes in the LH pattern during lamb growth. The data obtained provide evidence about the participation of kp in the mechanisms of ontogenic development of ovine reproductive processes.