The acylpolyamines from spider venoms

Acylpolyamines are low molecular mass toxins occurring exclusively in the venoms from solitary wasps and some groups of spiders. Their chemical structures have been elucidated using hyphenated techniques of mass spectrometry, such as LC-MS and MS/MS, or through direct analysis with different types of NMR analyses. The chemical structures of the acylpolyamine toxins from the venoms of Nephilinae orb-web spiders appear to be organized into four parts based on the combinatorial way that the chemical building blocks are bound to each other. An aromatic moiety (part I) is connected through a linker amino acid (part II) to a polyamine chain (part III), which in turn may be connected to an optional tail (part IV). The polyamine chains were classified into seven subtypes according to the different combinations of chemical building blocks. These polyamine chains, in turn, are connected to one of three chromophore moieties: a 2,4-dihydroxyphenyl acetyl group, a 4-hydroxyindolyl acetyl group, or an indolyl acetyl group. They may be connected through an asparagine residue or sometimes through the dipeptide ornithyl asparagine. Also, nine different types of backbone tails may be attached to the polyamine chains. These toxins are noncompetitive blockers of ionotropic glutamate receptors with neuroprotective action against the neuronal death and antiepileptic effect. Thus, compounds of this class of spider venom toxin seem to represent interesting molecular models for the development of novel neuropharmaceutical drugs. © 2012 Elsevier B.V. All rights reserved.

Investigação dos efeitos protetores do selenito de sódio sobre a neurotoxicidade do metilmercúrio em diferentes períodos de desenvolvimento de ratos wistar

A exposição a compostos mercuriais resulta em danos oxidativos, afetando gravemente o sistema nervoso central, como observado em humanos e em modelos experimentais. Este trabalho utilizou ratos Wistar em diferentes períodos do neuro-desenvolvimento a fim de investigar possíveis efeitos protetores do selênio (selenito de sódio) em um modelo in vivo de exposição ao metilmercúrio (MeHg). Os sujeitos (grupos de idades P1 e P21) receberam por amamentação ou via oral: veículo, Selênio (5ppm), MeHg (10ppm) ou Selênio (5ppm) mais MeHg (10ppm) durante 20 e 10 dias respectivamente (n = 8 por grupo). Após o tratamento, os ratos foram submetidos aos testes de campo aberto e labirinto aquático a fim de analisar déficits motores e de memória/aprendizagem, respectivamente. Para fins de análise histológica, foi realizada perfusão e imunohistoquimica para Neu-N. Com o objetivo de aferir possíveis efeitos deletérios sobre populações neuronais, foi feita contagem estereológica dos neurônios do hipocampo (camada polimórfica do giro denteado). Como resultado, foi observada redução significativa na atividade locomotora de neonatos (P1) mediante exposição ao MeHg. Além disso, nos grupos expostos ao MeHg (isoladamente ou associado ao selênio) verificou-se déficits de aprendizagem e memória. Já os animais P21 expostos ao MeHg apresentaram aumento na atividade locomotora, efeito abolido pela administração concomitante de selênio. Quando submetidos ao labirinto aquático, observou-se redução do tempo de latência apenas no grupo controle e naqueles animais expostos ao selênio. Como resultado das contagens estereológicas, observou-se diminuição do número de neurônios no hipocampo somente nos animais P21 expostos ao mercúrio. Os resultados obtidos sob estas condições experimentais mostraram que a exposição ao MeHg resultou em efeitos comportamentais diversos dependentes da idade dos sujeitos. A administração de selênio só foi capaz de interferir positivamente nos déficits locomotores observados em animais mais velhos. Além disso, foi observado que a administração de selênio não interferiu nos distúrbios comportamentais de memória/aprendizagem, tampouco na morte neuronal induzida por MeHg. Possíveis mecanismos associados a este padrão de proteção parcial por selênio, especialmente em estágios mais avançados de desenvolvimento neural ainda necessitam ser elucidados.

Alterações oxidativas em portadores de doença de Parkinson: correlação com critérios clínicos e estágios da doença

A doença de Parkinson (DP) constitui uma das mais prevalentes doenças neurológicas. Nesta doença, ocorre a neurodegeneração do sistema nigroestriatal com alteração da circuitaria neuronal dos núcleos da base levando ao comprometimento motor característico da doença. Os sintomas clássicos são o tremor de repouso, rigidez, acinesia ou bradicinesia e instabilidade postural. A patogênese da DP ainda permanece obscura. No entanto, estima-se que a disfunção mitocondrial e o desenvolvimento de estresse oxidativo na substância negra tenham papel relevante neste processo. O diagnóstico da DP é clinico e normalmente acontece tardiamente, quando a maioria dos neurônios nigrais está degenerada. Alguns trabalhos mostram o efeito neuroprotetor de medicações antiparkinsonianas e isto demonstra que quanto mais precoce a introdução do tratamento melhor o prognóstico à longo prazo da doença. Portanto o desenvolvimento de marcadores periféricos que ajudem no diagnóstico precoce da doença é importante para que se inicie o tratamento a tempo de retardar o avanço da morte neuronal. O objetivo deste trabalho foi verificar a existência de alterações em parâmetros oxidantes e antioxidantes no sangue de pacientes parkinsonianos e sua relação com o estágio da doença e critérios clínicos. Foram avaliados 30 portadores de DP e 30 indivíduos sem a doença. Para avaliar o estágio da doença e caracteres clínicos foram aplicadas as escalas de Hoehn & Yahr e a UPDRS (escala unificada para doença de Parkinson) nos pacientes parkinsonianos. Para avaliar a atividade oxidativa no plasma dos individuos, foi analisada a peroxidação lipídica através da mensuração de produtos da ação de Espécies Reativas de Oxigênio e Nitrogênio (ERON; TBARS) e para avaliar a resposta antioxidante foi feita a avaliação da Capacidade Antioxidante Total (TEAC). Nos grupos DP leve e DP moderado foi encontrado maior valor do TBARS e menor valor do TEAC em relação aos controles e DP grave (p<0,05), confirmando a presença de estresse oxidativo nas fases precoces da DP. Nesta pesquisa esses parâmetros demonstraram serem bons marcadores periféricos do estresse oxidativo, colaborando para um diagnóstico precoce da DP.

Análise citogenética como bioindicador para pacientes com diagnóstico sugestivo de Alzheimer

A doença de Alzheimer (DA) é uma doença neurodegenerativa que provoca morte neuronal e consequente perda progressiva das funções cognitivas, reduzindo as capacidades de trabalho, interferindo na relação social e no comportamento do paciente. Entre as doenças causadoras de demência, a DA é a mais incidente que as de cunho vascular, numa proporção de 4:1, respectivamente. Além das terapias farmacológicas, os métodos diagnósticos auxiliam na identificação precoce da doença auxiliando o tratamento prévio, assim diminuído a progressão da doença. Atualmente estudos citogenéticos vêm demonstrando alterações cromossômicas em portadoras da DA e podem auxiliar no diagnósticos da doença. O objetivo desse trabalho foi verificar o potencial da análise cariotípica de linfócitos do sangue periférico como bioindicador diagnostico da doença de Alzheimer. Para a realização deste trabalho, utilizamos dois grupos de mulheres com 65 anos ou mais, sendo um grupo com (10) portadoras de DA e outro grupo (10) normais. Cada indivíduo foi submetida ao questionário socioeconômico, teste de rastreio cognitivo (MEEM) e à coleta de sangue venoso para cultura de linfócitos e análise cromossômica. Nossos resultados demonstram que o grupo de mulheres portadoras da DA apresentaram elevada taxa de monossomia e trissomia em relação às mulheres normais. Através de estudo de anamnese via questionário, verificamos o estilo de vida de ambos os grupos. Quando comparado a relação das alterações cromossômicas com o nível cognitivo do grupo DA, nós evidenciamos uma tendência inversamente proporcional entre o número de monossomia/trissomia e o desempenho cognitivo. Outro aspecto de nossas análises foi o papel de cada cromossomo ligado à DA. Os cromossomos 1, 14 e 21 não apresentaram trissomia e na verificação da frequência de monossomia, cada cromossomo possui frequência abaixo de 3 % de aneuploidia, ou seja, os cromossomos estudados não possuem uma grande representatividade nas alterações cromossômicas encontradas no estudo.

Efeito protetor da flavana extraída da espécie Brosimum acutifolium contra danos causados por hipóxia em células retinianas: um estudo in vitro

O acidente vascular cerebral isquêmico (AVCi) causa danos celulares por provocar intensa excitotoxicidade e estresse oxidativo após privação de oxigênio e glicose para uma região do encéfalo. Neste trabalho, investigamos o potencial neuroprotetor da planta amazônica Brosimum acutifolium que é rica em flavanas como a 4',7-diidroxi-8-(3,3-dimetilalil)flavana (brosimina b, aqui abreviada como Bb) que apresenta elevado potencial antioxidante. Utilizamos cultura de células retinianas de embrião de galinha submetidas a hipóxia experimental, por privação de oxigênio e glicose, para avaliarmos o potencial antioxidante da Bb através da análise do sequestro do radical 2,2-difenil-1-picril-hidrazil (DPPH). Além disso, avaliamos a viabilidade celular (VC) e o perfil oxidativo e antioxidativo após 3, 6 e 24 horas de hipóxia, pela produção de oxigênio reativo (O₂^-) e atividade antioxidante endógena pela enzima catalase, respectivamente. Nossos resultados demonstram que nosso modelo experimental de hipóxia in vitro provoca redução tempo-dependente da VC, acompanhada por intenso estrese oxidativo, devido à excessiva produção de oxigênio reativo (O₂^-). O tratamento com Bb (10μM) protegeu significativamente a viabilidade celular durante 3 e 6 h de hipóxia experimental em células retiniana cultivadas in vitro, além de favorecer o aumento da atividade da enzima catalase em todos os tempos testados. Desta forma, concluímos que a Bb possui ação antioxidante e neuroprotetor por contribuir na defesa contra o estresse oxidativo induzido em condições de hipóxia, tornando-se como uma droga com potencial uso em tratamentos em casos de AVCi in vivo.

Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis

Although melatonin is mainly produced by the pineal gland, an increasing number of extra-pineal sites of melatonin synthesis have been described. We previously demonstrated the existence of bidirectional communication between the pineal gland and the immune system that drives a switch in melatonin production from the pineal gland to peripheral organs during the mounting of an innate immune response. In the present study, we show that acute neuroinflammation induced by lipopolysaccharide (LPS) injected directly into the lateral ventricles of adult rats reduces the nocturnal peak of melatonin in the plasma and induces its synthesis in the cerebellum, though not in the cortex or hippocampus. This increase in cerebellar melatonin content requires the activation of nuclear factor kappa B (NF-κB), which positively regulates the expression of the key enzyme for melatonin synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Interestingly, LPS treatment led to neuronal death in the hippocampus and cortex, but not in the cerebellum. This privileged protection of cerebellar cells was abrogated when G-protein-coupled melatonin receptors were blocked by the melatonin antagonist luzindole, suggesting that the local production of melatonin protects cerebellar neurons from LPS toxicity. This is the first demonstration of a switch between pineal and extra-pineal melatonin production in the central nervous system following a neuroinflammatory response. These results have direct implications concerning the differential susceptibility of specific brain areas to neuronal death.

Comparative analysis of the replication of bovine herpesvirus 1 (BHV1) and BHV5 in bovine derived-neuron-like cells

Members of the subfamily Alphaherpesvirinae use the epithelium of the upper respiratory and/or genital tract as preferential sites for primary replication. However, bovine herpesvirus 5 (BoHV5) is neurotropic and neuroinvasive and responsible for meningoencephalitis in cattle and in animal models. A related virus, BoHV1 has also been occasionally implicated in natural cases of neurological infection and disease in cattle. The aim of the present study was to assess the in vitro effects of BoHV1 and BoHV5 replication in neuron-like cells. Overall, cytopathic effects, consisting of floating rounded cells, giant cells and monolayer lysis, induced by both viruses at 48 h postinfection (p.i.) resulted in a loss of cell viability and high virus titres (r = 0.978). The BoHV1 Cooper strain produced the lowest titres in neuron-like cells, although viral DNA was detected in infected cells during all experiments. Virus replication in infected cells was demonstrated by immunocytochemistry, flow cytometry and qPCR assays. BoHV antigens were better visualized at 48 h p.i. and flow cytometry analysis showed that SV56/90 and Los Angeles antigens were present at higher levels. In spite of the fact that BoHV titres dropped at 48 h p.i, viral DNA remained detectable until 120 h p.i. Sensitive TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) and annexin V assays were used to identify apoptosis. BoHV5 induced death in approximately 50 % of cells within 24 h p.i., similar to what has been observed for BoHV1 Los Angeles. Infection with the BoHV1 Cooper strain resulted in 26.37 % of cells being in the early stages of apoptosis; 63.69 % of infected cells were considered viable. Modulation of mitochondrial function, as measured by mitochondrial membrane depolarization, was synchronous with the virus replication cycle, cell viability and virus titres at 48 h p.i. Our results indicate that apoptosis plays an important role in preventing neuronal death and provides a bovine-derived in vitro system to study herpesvirus-neuron interactions.

Increased Metallothionein I/II Expression in Patients with Temporal Lobe Epilepsy

In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and patients with TLE associated with tumor or dysplasia (TLE-TD) were evaluated for expression of MT-I/II, for the vesicular zinc levels, and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis, microgliosis and reduced neuronal population. In TLE-TD, the same changes were observed, except that were mainly confined to fascia dentata. Increased vesicular zinc was observed only in the inner molecular layer of MTLE patients, when compared to control cases. Correlation and linear regression analyses indicated an association between increased MT-I/II and increased astrogliosis in TLE. MT-I/II levels did not correlate with any clinical variables, but MTLE patients with secondary generalized seizures (SGS) had less MT-I/II than MTLE patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from TLE patients and our data suggest that it is associated with astrogliosis and may be associated with different seizure spread patterns.

Neurotoxicity of Anhydroecgonine Methyl Ester, a Crack Cocaine Pyrolysis Product

Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaineAEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME-induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaineAEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after cocaine use alone.

Different levels of MT-I/II between patients with MTLE with or without seizure generalization: does hippocampal MT-I/II affects seizure spread, or does seizure spread promotes differential expression of MT-I/II?

In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) were evaluated for expression of MT-I/II and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis and reduced neuronal population. MT-I/II levels did not correlate with any clinical variables, but patients with secondary generalized seizures (SGS) had less MT-I/II than patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from MTLE patients and our data suggest that it may be associated with different seizure spread patterns.

Effects of ischemia and reperfusion on subpopulations of rat enteric neurons expressing the P2X7 receptor

BACKGROUND: Intestinal ischemia followed by reperfusion (I/R) may occur following intestinal obstruction. In rats, I/R in the small intestine leads to structural changes accompanied by neuronal death. AIM: To analyze the impact of I/R injury on different neuronal populations in the myenteric plexus of rat ileum. METHODS: The ileal artery was occluded for 35 min and animals were euthanized 6, 24, and 72 h, and 1 week later. Immunohistochemistry was performed with antibodies against the P2X7 receptor as well as nitric oxide synthase (NOS), calbindin, calretinin, choline acetyltransferase (ChAT), or the pan-neuronal marker anti-HuC/D. RESULTS: Double immunolabeling demonstrated that 100% of NOS-, calbindin-, calretinin-, and ChAT-immunoreactive neurons in all groups expressed the P2X7 receptor. Following I/R, neuronal density decreased by 22.6% in P2X7 receptor-immunoreactive neurons, and decreased by 46.7, 38, 39.8, 21.7, and 20% in NOS-, calbindin-, calretinin-, ChAT-, and HuC/D-immunoreactive neurons, respectively, at 6, 24, and 72 h and 1 week following injury compared to the control and sham groups. We also observed a 14% increase in the neuronal cell body profile area of the NOS-immunoreactive neurons at 6 and 24 h post-I/R and a 14% increase in ChAT-immunoreactive neurons at 1 week following I/R. However, the average size of the calretinin-immunoreactive neurons was reduced by 12% at 6 h post-I/R and increased by 8% at 24 h post-I/R. CONCLUSIONS: This work demonstrates that I/R is associated with a significant loss of different subpopulations of neurons in the myenteric plexus accompanied by morphological changes, all of which may underlie conditions related to intestinal motility disorder

Neuroprotective activity of guanosine in an in vitro model of Alzheimer's disease

The β-Amyloid (βA) peptide is the major component of senile plaques that are one of the hallmarks of Alzheimer’s Disease (AD). It is well recognized that Aβ exists in multiple assembly states, such as soluble oligomers or insoluble fibrils, which affect neuronal viability and may contribute to disease progression. In particular, common βA-neurotoxic mechanisms are Ca2+ dyshomeostasis, reactive oxygen species (ROS) formation, altered signaling, mitochondrial dysfunction and neuronal death such as necrosis and apoptosis. Recent study shows that the ubiquitin-proteasome pathway play a crucial role in the degradation of short-lived and regulatory proteins that are important in a variety of basic and pathological cellular processes including apoptosis. Guanosine (Guo) is a purine nucleoside present extracellularly in brain that shows a spectrum of biological activities, both under physiological and pathological conditions. Recently it has become recognized that both neurons and glia also release guanine-based purines. However, the role of Guo in AD is still not well established. In this study, we investigated the machanism basis of neuroprotective effects of GUO against Aβ peptide-induced toxicity in neuronal (SH-SY5Y), in terms of mitochondrial dysfunction and translocation of phosphatidylserine (PS), a marker of apoptosis, using MTT and Annexin-V assay, respectively. In particular, treatment of SH-SY5Y cells with GUO (12,5-75 μM) in presence of monomeric βA25-35 (neurotoxic core of Aβ), oligomeric and fibrillar βA1-42 peptides showed a strong dose-dependent inhibitory effects on βA-induced toxic events. The maximum inhibition of mitochondrial function loss and PS translocation was observed with 75 μM of Guo. Subsequently, to investigate whether neuroprotection of Guo can be ascribed to its ability to modulate proteasome activity levels, we used lactacystin, a specific inhibitor of proteasome. We found that the antiapoptotic effects of Guo were completely abolished by lactacystin. To rule out the possibility that this effects resulted from an increase in proteasome activity by Guo, the chymotrypsin-like activity was assessed employing the fluorogenic substrate Z-LLL-AMC. The treatment of SH-SY5Y with Guo (75 μM for 0-6 h) induced a strong increase, in a time-dependent manner, of proteasome activity. In parallel, no increase of ubiquitinated protein levels was observed at similar experimental conditions adopted. We then evaluated an involvement of anti and pro-apoptotic proteins such as Bcl-2, Bad and Bax by western blot analysis. Interestingly, Bax levels decreased after 2 h treatment of SH-SY5Y with Guo. Taken together, these results demonstrate that Guo neuroprotective effects against βA-induced apoptosis are mediated, at least partly, via proteasome activation. In particular, these findings suggest a novel neuroprotective pathway mediated by Guo, which involves a rapid degradation of pro-apoptotic proteins by the proteasome. In conclusion, the present data, raise the possibility that Guo could be used as an agent for the treatment of AD.

Neurodegenerative diseases: molecular mechanisms and new strategies for neuroprotection

The term neurodegeneration defines numerous conditions that modify neuron’s normal functions in the human brain where is possible to observe a progressive and consistent neuronal loss. The mechanisms involved in neurodegenerative chronic and acute diseases evolution are not completely understood yet, however they share common characteristics such as misfolded proteins, oxidative stress, inflammation, excitotoxicity, and neuronal loss. Many studies have shown the frequency to develop neurodegenerative chronic diseases several years after an acute brain injury. In addition, many patients show, after a traumatic brain injury, motor and cognitive manifestations that are close to which are observed in neurodegenerative chronic patients. For this reason it is evident how is fundamental the concept of neuroprotection as a way to modulate the neurodegenerative processes evolution. Neuroinflammation, oxidative stress and the apoptotic process may be functional targets where operate to this end. Taking into account these considerations, the aim of the present study is to identify potential common pathogenetic pathways in neurodegenerative diseases using an integrated approach of preclinical studies. The goal is to delineate therapeutic strategies for the prevention of neuroinflammation, neurodegeneration and dysfunctions associated to Parkinson’s disease (PD) and cerebral ischemia. In the present study we used a murine model of PD treated with an isothiocyanate, 6-MSITC, able to quench ROS formation, restore the antioxidant GSH system, slow down the apoptotic neuronal death and counteract motor dysfunction induced by 6-OHDA. In the second study we utilized a transgenic mouse model knockout for CD36 receptor to investigate the inflammation involvement in a long term study of MCAo, which shows a better outcome after the damage induced. In conclusion, results in this study allow underlying the connection among these pathologies, and the importance of a neuroprotective strategy able to restore neurons activity where current drugs therapies have shown palliative but not healing abilities.

Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

Neuroprotective effect of excitatory amino acid antagonist kynurenic acid in experimental bacterial meningitis

Sustained high-level exposure to glutamate, an excitatory amino acid neurotransmitter, leads to neuronal death. Kynurenic acid attenuates the toxic effects of glutamate by inhibition of neuronal excitatory amino acid receptors, including the N-methyl-D-aspartate subtype. To evaluate the role of glutamate in causing neuronal injury in a rat model of meningitis due to group B streptococci, animals were treated with kynurenic acid (300 mg/kg subcutaneously once daily) or saline beginning at the time of infection. Histopathologic examination after 24-72 h showed two distinct forms of neuronal injury, areas of neuronal necrosis in the cortex and injury of dentate granule cells in the hippocampus. Animals treated with kynurenic acid showed significantly less neuronal injury (P < .03) in the cortex and the hippocampus than did untreated controls. These results suggest an important contribution of glutamate to neurotoxicity in this animal model of neonatal meningitis.