Neurotropic Agents Research Articles

The scientific school of pharmacology of S.V. Anichkov, an academician of the USSR academy of medical sciences

Sergei V. Anichkov (1892–1981) is a Doctor of Medical Sciences, Professor, Academician of the USSR Academy of Medical Sciences, and laureate of the Lenin and USSR State Prizes, led the Department of Pharmacology at the Institute of Experimental Medicine from 1948 to 1981. Initially, the department comprised three laboratories with a limited staff. To advance research, Anichkov, who headed the Department of Pharmacology at the Sanitary and Hygienic Medical Institute, brought together the resources of this Department and the Department of Pharmacology of the Institute of Experimental Medicine, further expanding them, primarily through the addition of postgraduate students such as S.S. Krylov, P.P. Denisenko, V.G. Startsev, V.E. Ryzhenkov, Yu.S. Borodkin, I.S. Zavodskaya, and others. Anichkov established a scientific school of pharmacologists, and many significant achievements of the Department of Pharmacology at the Institute of Experimental Medicine are associated with his name. Young postgraduate students, passionate about research work, became the first or senior disciples and followers of the scientific school of pharmacology of academician Anichkov. Clinical and experimental studies conducted on the use of neurotropic agents for the treatment of gastroduodenal and cardiovascular disorders made it possible to propose a fundamentally new approach to treating peptic ulcer disease, ischemic heart disease, myocardial infarction, and tonsillogenic cardiopathies, depending on specific conditions and stages of the disease. It was substantiated that the administration of neuroblockers to patients is advisable only in the acute phase of the disease, when there is an excessive flow of nerve impulses that cause and maintain the pathological process. However, when acute symptoms cease and the reparative phase begins, the suppression of nerve impulses may slow down the reparative processes. At this stage, as indicated by experimental and clinical data, the use of agents that normalize the trophic function of the sympathoadrenal system and stimulate tissue energy metabolism is recommended. In 1946, Anichkov proposed to divide the cholinoreactive systems into muscarine-sensitive and nicotine-sensitive types. From that time, the pharmacology of central anticholinergics became an important issue for the Anichkov›s school for many years. A number of neurotropic drugs from various classes were proposed for the pharmacological treatment of hormonal disorders. One of them was the original drug Etimizol (Ethimizole), which activates the hypothalamus-pituitary-adrenal cortex system and increases the sensitivity of the adrenal cortex to the action of adrenocorticotropic hormone, which allowed the drug to be recommended for asthma and various inflammatory diseases.

Herpesvirus surveillance in stranded striped dolphins (Stenella coeruleoalba) and bottlenose dolphins (Tursiops truncatus) from Italy with emphasis on neuropathological characterization.

Herpesvirus (HV) is widely distributed among cetacean populations, with the highest prevalence reported in the Mediterranean Sea. In this study, a comprehensive analysis was conducted, including epidemiological, phylogenetic, and pathological aspects, with particular emphasis on neuropathology, to better understand the impact of HV in these animals. Our results show a higher presence of HV in males compared to females, with males exhibiting a greater number of positive tissues. Additionally, adults were more frequently affected by HV infection than juveniles, with no infections detected in calves or neonates. The affected species were striped (Stenella coeruleoalba) and bottlenose dolphins (Tursiops truncatus). The highest positivity rates were observed in the genital system, cerebrum, and skin tissues. Phylogenetic analysis indicated a higher occurrence of Gammaherpesvirus (GHV) sequences but increased genetic diversity within Alphaherpesvirus (AHV). Key neuropathological features included astro-microgliosis (n = 4) and meningitis with minimal to mild perivascular cuffing (n = 2). The presence of concurrent infections with other pathogens, particularly cetacean morbillivirus (CeMV), underscores the complex nature of infectious diseases in cetaceans. However, the presence of lesions at the Central Nervous System (CNS) with molecular positivity for GHV, excluding the involvement of other potential neurotropic agents, would confirm the potential of this HV subfamily to induce neurological damage. Pathological examination identified lesions in other organs that could potentially be associated with HV, characterized by lymphoid depletion and tissue inflammation. These findings enhance our understanding of HV in odontocetes and highlight the need for ongoing research into the factors driving these infections and their broader implications.

New triazole-based hybrids as neurotropic agents.

Herein, we describe the synthesis of new hybrids linked to 1,2,3- and 1,2,4-triazole units. Hybrids connected to a 1,2,3-triazole ring were synthesized using the well-known click reaction. The synthesis of the 1,2,4-triazole-based hybrids was carried out using 2-[(4-cyano-1-methyl(2-furyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetohydrazides as starting compounds. The compounds were evaluated for their anticonvulsive activity via antagonism towards pentylenetetrazole (PTZ) - and thiosemicarbazide (TSC)-induced convulsion and maximal electroshock-induced seizure (MES). Furthermore, the most active compounds were studied for their locomotory and anxiolytic activity via the "open field" and elevated plus maze (EPM) assays. Finally, their antidepressant activity was studied via the "forced swim" method. All the hybrids displayed pentylenetetrazole antagonism, ranging from 40% to 80%, while in the TSC model, the most active compounds increased latency of thiosemicarbazide seizures to 1.9-4.65 times compared to that of the control. Some of the tested compounds exhibited a pronounced anxiolytic and antidepressant effect. Docking study demonstrated complete agreement with experimental pharmacological data. It was revealed that the most active compounds have a pyrano[3,4-c]pyridine ring in their structure.

Using Zebrafish in Preclinical Drug Studies: Challenges and Opportunities

Scientific relevance. Since fiscal and regulatory constraints substantially limit bioscreening in rodent models, a wider implementation of additional alternative models in preclinical studies of medicines is gaining momentum. These alternative models include aquatic vertebrates, such as zebrafish (Danio rerio).Aim. The study aimed to examine zebrafish models in terms of their performance in preclinical studies, their current uses, the challenges and opportunities in the field, and strategic directions for the development of preclinical testing in zebrafish.Discussion. Here, the authors summarise the key zebrafish tests that are currently used to assess a wide range of small molecules for their general and endocrine toxicity and effects on the survival of embryos and larvae. The review discusses the strengths and weaknesses of zebrafish models for preclinical testing of neurotropic agents. Additionally, the authors overview various methodological approaches to improving zebrafish toxicity testing. Overall, the use of zebrafish models is gradually becoming internationally established for laboratory testing of small molecules.Conclusions. A wider implementation of zebrafish models in pharmaceutical research and preclinical testing as an additional alternative to rodents, particularly in Russia, may significantly accelerate the development of novel medicinal products and foster a more comprehensive and adequate assessment of the biological risks associated with chemical substances.

Noninvasive disruption of the blood-brain barrier in the marmoset monkey

The common marmoset monkey (Callithrix jacchus) is a species of rising prominence in the neurosciences due to its small size, ease of handling, fast breeding, and its shared functional and structural brain characteristics with Old World primates. With increasing attention on modeling human brain diseases in marmosets, understanding how to deliver therapeutic or neurotropic agents to the marmoset brain noninvasively is of great preclinical importance. In other species, including humans, transcranial focused ultrasound (tFUS) aided by intravenously injected microbubbles has proven to be a transient, reliable, and safe method for disrupting the blood-brain barrier (BBB), allowing the focal passage of therapeutic agents that do not otherwise readily traverse the tight endothelial junctions of the BBB. The critical gap that we address here is to document parameters to disrupt the BBB reliably and safely in marmosets using tFUS. By integrating our marmoset brain atlases and the use of a marmoset-specific stereotactic targeting system, we conduct a series of systematic transcranial sonication experiments in nine marmosets. We demonstrate the effects of center frequency, acoustic pressure, burst period, and duration, establish a minimum microbubble dose, estimate microbubble clearance time, and estimate the duration that the BBB remains open to passage. Successful BBB disruption is reported in vivo with MRI-based contrast agents, as well as Evans blue staining assessed ex vivo. Histology (Hematoxylin and Eosin staining) and immunohistochemistry indicate that the BBB can be safely and reliably opened with the parameters derived from these experiments. The series of experiments presented here establish methods for safely, reproducibly, and focally perturbing the BBB using tFUS in the common marmoset monkey that can serve as a basis for noninvasive delivery of therapeutic or neurotropic agents.

Group B vitamins: prospective for multidisciplinary application: A review

Group B vitamins are used in various fields of medicine, most commonly in treating diseases of the peripheral and central nervous system, especially in treating pain. Group B vitamins are neurotropic agents; they play an essential role in the functioning of cells, acting as coenzymes in a wide range of catabolic and anabolic enzymatic reactions. They play a role in numerous processes of nervous tissue functioning, including energy production, DNA/RNA synthesis/repair, genomic and non-genomic methylation, and synthesis of many neurochemicals and signaling molecules, which ensures the normal functioning of the central and peripheral nervous system. Among all the B vitamins, these properties are most inherent in thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12).

The effects of heavy metals on the developing brain

The analysis shows that there are disproportionately few works on the mentioned joint effects of HMs in relation to the importance of this issue. It was found that the joint administration of HMs with each other and under stress increases the neurotoxic effect of metals on the brain of animals. A greater vulnerability to the neurotoxic effects of HM mixtures on the developing brain was also noted. Neurotropic drugs in combination with HMs have multidirectional effects. Thus, along with the counteraction of the reference nootropic piracetam to the inhibition of the avoidance response in rats, which is exerted by HMs, there was an increase in the neurotoxic effects of lead and cadmium salts when combined with that nootropic. Combined administration of Semax (a regulatory peptide with nootropic effects) and molybdenum, which separately suppressed the avoidance response in rats, paradoxically improved learning and memory. The revealed unpredictability and enhancement of the neurotoxic effects of HMs when combined with neurotropic agents are fraught with danger to human health in regions with developed industries. This is especially important for the health of children due to the increased vulnerability of their developing brains to neurotoxicants.

Проблемы классификации и характеристика нейротропных средств, применяемых для терапии нарушений мозгового кровообращения

In developed countries, mortality from cerebrovascular diseases (CVD) is about 12%, which is second only to mortality from cardiovascular diseases. In order to make treatment of CVD successful, a complex approach to the problem is required with compensation for cardiovascular diseases (atherosclerosis, arterial hypertension, rheological properties of blood, etc.), elimination of neurological and psychopathological syndromes, improvement of cerebral circulation and use of neurotropic agents. The use of neurotropic agents by a practicing physician is complicated due to the lack of a clear classification reflecting their position and significance in CVD treatment. It is suggested that taking into account the predominant mechanism of action targeting for a pathological process, neurotropic agents should be divided into 4 groups such as neuroprotectors, neurometabolics, nootropics and neurotrophic agents (direct activators of neutrophin synthesis in the brain). The last group is related to analogues of regulatory peptides and shares positive properties with medicinal agents from other groups: they have the properties of primary and secondary neuroprotectors, neurometabolics, and produce a positive effect on cognitive functions of a healthy and sick person. Heptapeptide Semax is a typical agent belonging to this group.

Update on lyssaviruses and rabies: will past progress play as prologue in the near term towards future elimination?

Rabies is an ancient, much-feared, and neglected infectious disease. Caused by pathogens in the family Rhabdoviridae, genus Lyssavirus, and distributed globally, this viral zoonosis results in tens of thousands of human fatalities and millions of exposures annually. All mammals are believed susceptible, but only certain taxa act as reservoirs. Dependence upon direct routing to, replication within, and passage from the central nervous system serves as a basic viral strategy for perpetuation. By a combination of stealth and subversion, lyssaviruses are quintessential neurotropic agents and cause an acute, progressive encephalitis. No treatment exists, so prevention is the key. Although not a disease considered for eradication, something of a modern rebirth has been occurring within the field as of late with regard to detection, prevention, and management as well as applied research. For example, within the past decade, new lyssaviruses have been characterized; sensitive and specific diagnostics have been optimized; pure, potent, safe, and efficacious human biologics have improved human prophylaxis; regional efforts have controlled canine rabies by mass immunization; wildlife rabies has been controlled by oral rabies vaccination over large geographic areas in Europe and North America; and debate has resumed over the controversial topic of therapy. Based upon such progress to date, there are certain expectations for the next 10 years. These include pathogen discovery, to uncover additional lyssaviruses in the Old World; laboratory-based surveillance enhancement by simplified, rapid testing; anti-viral drug appearance, based upon an improved appreciation of viral pathobiology and host response; and improvements to canine rabies elimination regionally throughout Africa, Asia, and the Americas by application of the best technical, organizational, economic, and socio-political practices. Significantly, anticipated Gavi support will enable improved access of human rabies vaccines in lesser developed countries at a national level, with integrated bite management, dose-sparing regimens, and a 1 week vaccination schedule.

Infectious Causation of Abnormal Host Behavior: Toxoplasma gondii and Its Potential Association With Dopey Fox Syndrome.

The apicomplexan parasite Toxoplasma gondii, the causative agent of toxoplasmosis, can infect all warm-blooded animals. T. gondii can subtly alter host behaviors—either through manipulation to enhance transmission to the feline definitive host or as a side-effect, or “constraint,” of infection. In humans, T. gondii infection, either alone or in association with other co-infecting neurotropic agents, has been reliably associated with both subtle behavioral changes and, in some cases, severe neuropsychiatric disorders, including schizophrenia. Research on the potential impact of T. gondii on the behavior of other long-lived naturally infected hosts is lacking. Recent studies reported a large number of wild red foxes exhibiting a range of aberrant behavioral traits, subsequently classified as Dopey Fox Syndrome (DFS). Here we assessed the potential association between T. gondii and/or other neurotropic agents with DFS. Live, captive foxes within welfare centers were serologically tested for T. gondii and, if they died naturally, PCR-tested for vulpine circovirus (FoxCV). Post-mortem pseudo-control wild foxes, obtained from pest management companies, were PCR-tested for T. gondii, FoxCV, canine distemper virus (CDV), canine adenovirus type (CAV)-1 and CAV-2. We also assessed, using non-invasive assays, whether T. gondii–infected foxes showed subtle behavioral alterations as observed among infected rodent (and other) hosts, including altered activity, risk, and stress levels. All foxes tested negative for CAV, CDV, CHV, and DogCV. DFS was found to be associated with singular T. gondii infection (captives vs. pseudo-controls, 33.3% (3/9) vs. 6.8% (5/74)) and singular FoxCV infection (66.7% (6/9) vs. 11.1% (1/9)) and with T. gondii/FoxCV co-infection (33.3% (3/9) vs. 11.1% (1/9)). Overall, a higher proportion of captive foxes had signs of neuroinflammation compared to pseudo-controls (66.7% (4/6) vs. 11.1% (1/9)). Consistent with behavioral changes seen in infected rodents, T. gondii–infected foxes displayed increased attraction toward feline odor (n=6 foxes). These preliminary results suggest that wild foxes with DFS are infected with T. gondii and likely co-infected with FoxCV and/or another co-infecting neurotropic agent. Our findings using this novel system have important implications for our understanding of both the impact of parasites on mammalian host behavior in general and, potentially, of the infectious causation of certain neuropsychiatric disorders.

EFFECTS OF SILVER NANOPARTICLES ON PENTYLENETETRAZOL-INDUCED KINDLED SEIZURES IN RATS

Silver nanoparticles are used for delivering neurotropic agents to brain, increasing the bioavailability of insoluble drugs as well as for brain tumours treatment. Their effects upon brain excitability, especially under conditions of chronic epilepsy modelling are underinvestigated. The purpose of the study was to study the effects of silver nanoparticles upon pentylenetetrazol-induced kindled seizures in rats. Material and Methods. Experiments were performed on Wistar rats kindled during four weeks with pentylenetetrazol administrations in a dose of 30.0 mg/kg, i.p. Only rats, which demonstrated generalized clonic-tonic seizures in a response to each of three last epileptogen injections, were included into the study. Nanoparticles and ionized argentum were administered in a dosage of 0.2 mg/kg, i.p. Observation was performed in early and postponed period of kindling – in 24 h and three weeks from the moment of kindling induction, correspondently. Results and discussion. The calculation of the pentylenetetrazol dose, which effectively induced seizures in 50 % of kindled rats (ED50), was performed in kindled animals in 24 h from the moment of last epileptogen administration was 22.0 mg/kg. In postponed period of kindling (three weeks from the moment of last pentylenetetrazol administration in a dose of 30.0 mg/kg, i.p.), ED50 of pentylenetetrazol was 16.0 mg/kg. ED50 of pentylenetetrazol, which induced clonic seizures in 50 % animals at the early stage of kindling, was recalculated following the administration of ionized and nanoparticle forms of silver, and were less when compared with such ones determined in the control group by 13.5 % (P>0,05) and 26.0 % (P<0,05), respectively. In the postponed period of kindling ED50 of ionized and nanoparticle forms of silver were less when compared with control by 20.0 % (P<0.05) and by 42.0 %, respectively (P<0.05). Significant difference was noted between groups treated with ionized and nanoparticle silver (P<0.05). The net intensification of pentylenetetrazol seizure manifestations was seen in kindled rats treated with silver nanoparticles, when seizure discharges amplitude achieved 1.0-1.2 mV and frequency of 3/sec, which exceeded the ones in rats treated with ionized silver. Conclusion. Silver nanoparticles induce the increase in seizures severity in pentylenetetrazol-kindled rats, and this effect was more pronounced at the postponed stage of kindling development.

1680. Guillain Barré Syndrome in Arbovirus Outbreak in Veracruz, Mexico: The Follow-up to 3 Years of the Pandemic

BackgroundFrom the arrival of Zika to America in 2015, and the increase in cases of Guillain sweeten in South America apparently associated with acute viral infection, Mexico had its first contact in 2016, with an increase in the incidence of cases of the syndrome, initiating a protocol study to look for the causal association of the Zika virus syndromeMethodsWe conducted a descriptive, prospective, and longitudinal study in Veracruz, Mexico, where follow-up of cases of Guillain Barre Syndrome (GBS) occurred during 2016 to 2018. The central point of the study is to look for the etiological association of GBS with the presence of acute zika infection. Secondarily, other know neutropic agents, both viral and bacterial were searched. The diagnosis techniques used were PCR-RT (blood and urine) and IgM/IgG for Zika; serum PCR-RT and IgM/IgG for Dengue and Chikungunya; IgM/IgG for TORCH; PCR-RT in CSF for Herpes and Enterovirus; serological panel of Hepatitis B and C; PCR-RT in rectal swab for Campylobacter.ResultsA cohort of 39 patients has been formed over 3 years of study. 38 patients met the operational definition of a suspected case of Zika, of which only 2 cases were identified by PCR-RT in urine; During the search protocol for infectious agents, others were identified such as: Dengue, Chikungunya, Enterovirus, Herpes and Hepatitis B; however, the identification of Campylobacter was even more remarkable, also highlighting that only four patients had diarrhea. Regarding the treatment, 37 patients received IVIG, 1 patient received plasmapheresis and 1 patient received both. The prognosis was good in 34 patients (basal Hugues from 4–5 to 2), 5 had poor functional prognosis and died.ConclusionThe incidence of Zika as a cause of GBS is relatively low (5%), so the etiological association could not be demonstrated; other neurotropic viral agents were identified, however the presence of Campylobacter cases was more notable (asymptomatic campylobacteriosis). Disclosures All authors: No reported disclosures.

Synthesis and Biological Evaluation of Novel 2,3-disubstituted Benzofuran Analogues of GABA as Neurotropic Agents.

Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.

Post-infectious sensory neuropathy with anti-GT1a and GQ1b antibodies associated with cold urticaria

A 64 years-old woman presented subacute onset distal paraesthesia concurrently with cold-induced urticaria, a rare form of physical urticaria. Both the disturbances developed a fortnight after an upper respiratory tract infection. EMG confirmed an exclusively sensory polyneuropathy, with prolongation of distal latencies and reduction of amplitudes. Anti-GQ1b and anti-GT1a antigangliosides antibodies were found in serum. The clinical workout included CSF analysis, cryoglobulin and paraprotein search, neurotropic infective agents, neoplastic markers and extensive autoimmune disease antibodies analysis, all of which resulted negative. Intravenous immunoglobulins were administered, leading to progressive resolution of the sensory disturbance, while a combination of steroid and anti-histaminics treatment was used for the urticaria. The positivity for anti-ganglioside search with an EMG pattern characterized by a mixture of demyelinating and axonal features may suggest a nodo-paranodopathy at early stages. This is the first case of an association between an acute sensory neuropathy and cold urticaria, two immune mediated conditions apparently due to very different hypersensitivity pathways. A proposed mechanism for the co-occurence of these two conditions is presented, whereas this case expands the clinical spectrum of autoimmune diseases associated with anti-GQ1b and anti-GT1a antibodies.

Pharmacology and Toxicology of Polyphenols with Potential As Neurotropic Agents in Non-communicable Diseases.

The central nervous system (CNS) is involved in organic integration. Nervous modulation via bioactive compounds can modify metabolism in order to prevent systemic noncommunicable diseases (NCDs). Concerning this, plant polyphenols are proposed as neurotropic chemopreventive/ therapeutic agents, given their redox and regulating properties. To review polyphenolic pharmacology and potential neurological impact on NCDs. First, polyphenolic chemistry was presented, as well as pharmacology, i.e. kinetics and dynamics. Toxicology was particularly described. Then, functional relevance of these compounds was reviewed focusing on the metabolic CNS participation to modulate NCDs, with data being finally integrated. Oxidative stress is a major risk factor for NCDs. Polyphenols regulate the redox biology of different organic systems including the CNS, which participates in metabolic homeostasis. Polyphenolic neurotropism is determined by certain pharmacological characteristics, modifying nervous and systemic physiopathology, acting on several biological targets. Nonetheless, because these phytochemicals can trigger toxic effects, they should not be recommended indiscriminately. Summing up, the modulating effects of polyphenols allow for the physiological role of CNS on metabolism and organic integration to be utilized in order to prevent NCDs, without losing sight of the risks.

Modulation of Puberty Terms and Sexual Behavior of Rats after Prenatal Exposure to Methyldopa, Phenibut, and Stress

Prenatal effects of methyldopa, an inhibitor of noradrenaline synthesis (400 mg/kg/day), GABA agonist phenibut (100 mg/kg/day), or immobilization stress against the background of phenibut action on the timing of puberty and sexual behavior of male and female rats were investigated. The drugs were administered orally to pregnant animals during the last week of pregnancy (from the 15th to the 21st day). In experiments with prenatal stress, pregnant animals were immobilized daily for one hour during the same period of pregnancy. Some of them received phenibut 30 minutes prior to stressing. Application of phenibut to nonstressed pregnant animals led to accelerated maturation, and the use of methyldopa or phenibut resulted in disorders of sexual behavior of male and female offspring. However, phenibut weakened demasculinizing and feminizing effects of prenatal stress on male sexual behavior, as evidenced by the normalization of the latent periods of mountings and intromissions, their number, and a decrease in the number of lordosis reactions. Phenibut partially restored timing of puberty in those animals. The results obtained indicate the involvement of noradrenergic and GABA-ergic mechanisms in the prenatal programming of sexual behavior of animals, as well as the possibility of preventing its disorders in adult prenatally stressed rats by the activation of GABA-ergic receptors. Based on the results of these and previous studies, the concept of dualistic effects of hormonal and pharmacological neurotropic agents that are used during pregnancy has been proposed, according to which these agents may have either harmful or protective effect on the reproductive health and the ability of the offspring to respond to stressor factors.

Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents.

One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival, and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration. Here, we establish the existence of a unique family of methylene-cycloalkylacetate-based molecules (MCAs) that interface with neuronal cell properties and operate as acceptable pharmacophores for a novel neurotropic (neurite outgrowth inducing) lead compounds. Using an established PC12 cell bioassay, we investigated the neurotropic effect of methylene-cycloalkylacetate compounds by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by using a light microscope camera, and digitized photographs were analyzed for compound-induced neurotropic activity using an NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. The discovered lead compounds need further mechanistic investigation and may be improved toward development of a neurotropic drug.

The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small?

The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.

Expanding the tetrahydroquinoline pharmacophore

Tetrahydroquinoline is a privileged scaffold with a large number of biological applications. The tetrahydroquinoline pharmacophore has been expanded to yield 34 compounds. Biological screening of these compounds led to the identification of tetrahydroquinoline as neurotropic agents not reported earlier.

Suicide attempts and markers of immune response in individuals with serious mental illness

Previous studies have identified elevations in antibodies to Toxoplasma gondii in individuals with a history of suicide attempts but studies have not measured the association between suicide attempts and a panel of antibody markers. We assessed 162 patients receiving treatment for schizophrenia, bipolar disorder, or major depression on the Columbia Suicide Severity Rating Scale for suicide attempt history and other clinical measures. All participants had a blood sample drawn from which were measured antibodies to Toxoplasma gondii and other neurotropic infectious agents. A total of 72 (44%) of participants had a lifetime suicide attempt; these individuals had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV). We also found an association between the levels of these antibodies and the number of suicide attempts. There was a particularly strong odds of a suicide attempt history in individuals who had elevated levels of IgM antibodies to both Toxoplasma gondii and to CMV suggesting an additive risk associated with the antibodies. These findings remained significant when adjusting for current cigarette smoking and history of drug/alcohol use which were also associated with suicide attempts. We did not find an association between a suicide attempt history and IgG class antibodies to Toxoplasma gondii, CMV, or IgM or IgG antibodies to the Epstein Barr Virus or other antigens tested. The identification of blood-based antibody markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.