Single amyloid-beta injection exacerbates 4-aminopyridine-induced seizures and changes synaptic coupling in the hippocampus.

Accumulation of amyloid-beta (Aß) in temporal lobe structures, including the hippocampus, is related to a variety of Alzheimer's disease symptoms and seems to be involved in the induction of neural network hyperexcitability and even seizures. Still, a direct evaluation of the pro-epileptogenic effects of Aß in vivo, and of the underlying mechanisms, is missing. Thus, we tested whether the intracisternal injection of Aß modulates 4-aminopyridine (4AP)-induced epileptiform activity, hippocampal network function, and its synaptic coupling. When tested 3 weeks after its administration, Aß (but not its vehicle) reduces the latency for 4AP-induced seizures, increases the number of generalized seizures, exacerbates the time to fully recover from seizures, and favors seizure-induced death. These pro-epileptogenic effects of Aß correlate with a reduction in the power of the spontaneous hippocampal network activity, involving all frequency bands in vivo and only the theta band (4-10 Hz) in vitro. The pro-epileptogenic effects of Aß also correlate with a reduction of the Schaffer-collateral CA1 synaptic coupling in vitro, which is exacerbated by the sequential bath application of 4-AP and Aß. In summary, Aß produces long-lasting pro-epileptic effects that can be due to alterations in the hippocampal circuit, impacting its coordinated network activity and its synaptic efficiency. It is likely that normalizing synaptic coupling and/or coordinated neural network activity (i.e., theta activity) may contribute not only to improve cognitive function in Alzheimer's disease but also to avoid hyperexcitation in conditions of amyloidosis.

Comparative study of intracisternal kaolin injection techniques to induce congenital hydrocephalus in fetal lamb.

PURPOSE: Kaolin (aluminum silicate) has been used to generate hydrocephalus by direct cisterna magna injection in animal models. The aim of the present study is to compare which method of Kaolin injection into fetal cisterna magna is feasible, safer, and more effective to induce hydrocephalus in fetal lambs. METHODS: Twenty-five well-dated pregnant ewes at gestational 85-90 days (E85-90) were used to compare three different kaolin injection puncture techniques into the fetal cisterna magna. Group 1, ultrasound guidance in a maternal percutaneous transabdominal (TA); group 2, without opening the uterus in a transuterine (TU) technique; group 3, by occipital direct access after exteriorizing fetal head (EFH); and group 4, control group, was normal fetal lambs without injection. The fetal lambs were assessed using lateral ventricle diameter ultrasonographic measurements prior the kaolin injection and on the subsequent days. We analyzed the effectivity, mortality, and fetal losses to determine the best technique to create hydrocephalus in fetal lamb. RESULTS: After fetal intracisternal kaolin (2%, 1mL) injection, lateral ventricle diameters increased progressively in the three different interventional groups compared with the normal values of the control group (p ≤ 0.05). We observed that the transabdominal method had a 60% of fetal losses, considering failure of injection and mortality, compared with the 12.5% in the open group (EFH), and 0% for the transuterine group. CONCLUSIONS: Based on our study, we believe that both, open uterine (EFH) and transuterine approaches are more effective and safer than the transabdominal ultrasound-guided method to induce hydrocephalus.

Reduced spinal cord parenchymal cerebrospinal fluid circulation in experimental autoimmune encephalomyelitis.

An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna, we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.

Endoscopic ventriculo-cisterno-ventricular approach in the treatment of bilateral trapped temporal horn related to fungal infection in a child: case report and review of the literature.

INTRODUCTION: Focal hydrocephalus including trapped temporal horn (TTH), isolated lateral and fourth ventricles, is caused by obstruction and/or adhesion related to various etiologies. With the advent of the neuroendoscope, endoscopic procedures have become an alternative in selected cases. CASE REPORT: A 2-year-old male from a rural town in México was referred to our institution because of multiple supra- and infra-tentorial abscesses and hydrocephalus. The patient had progressive deterioration and developed bilateral trapped temporal horn related to multi-septated hydrocephalus, so we performed an endoscopic ventricular-cistern-ventriculostomy through a single right temporal burr hole. POSTOPERATIVE COURSE: Bilateral TTH and multi-septated hydrocephalus were effectively treated with a single external ventricular drainage (EVD) catheter, from the right temporal horn to the left temporal horn through the interpeduncular cistern; after clamping the EVD for 3 days with no evidence of hydrocephalus, the EVD was removed. The size of the ventricles remained stable afterwards, and no clinical or radiological evidence of hydrocephalus was observed after 3 months of follow-up. DISCUSSION: Endoscopic ventriculocisternostomy is effective in selected cases of TTH. We know that dilatation of the temporal horn widens the window between the anterior choroidal artery and optic tract superiorly, and the posterior communicating and CN III inferiorly, making the described procedure feasible, even in the approach to the contralateral side. Even though this is a rare condition, we believe it is a safe and effective option to eliminate multiple shunts and/or to reduce the number of catheters needed to treat bilateral THH related to multi-septated hydrocephalus.

Transduction Profile of the Marmoset Central Nervous System Using Adeno-Associated Virus Serotype 9 Vectors.

The common marmoset is a small New World primate that has attracted remarkable attention as a potential experimental animal link between rodents and humans. Adeno-associated virus (AAV) vector-mediated expression of a disease-causing gene or a potential therapeutic gene in the brain may allow the construction of a marmoset model of a brain disorder or an exploration of the possibility of gene therapy. To gain more insights into AAV vector-mediated transduction profiles in the marmoset central nervous system (CNS), we delivered AAV serotype 9 (AAV9) vectors expressing GFP to the cisterna magna or the cerebellar cortex. Intracisternally injected AAV9 vectors expanded in the CNS according to the cerebrospinal fluid (CSF) flow, by retrograde transport through neuronal axons or via intermediary transcytosis, resulting in diffuse and global transduction within the CNS. In contrast, cerebellar parenchymal injection intensely transduced a more limited area, including the cerebellar cortex and cerebellar afferents, such as neurons of the pontine nuclei, vestibular nucleus and inferior olivary nucleus. In the spinal cord, both administration routes resulted in labeling of the dorsal column and spinocerebellar tracts, presumably by retrograde transport from the medulla oblongata and cerebellum, respectively. Motor neurons and dorsal root ganglia were also transduced, possibly by diffusion of the vector down the subarachnoid space along the cord. Thus, these two administration routes led to distinct transduction patterns in the marmoset CNS, which could be utilized to generate different disease animal models and to deliver therapeutic genes for the treatment of diseases affecting distinct brain areas.

Vascular basement membranes as pathways for the passage of fluid into and out of the brain.

In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aß, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aß was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.

Congenital microtia in a neonate due to maternal isotretinoin exposure 1 month before pregnancy: Case Report.

Isotretinoin is a drug used for treating severe cystic/nodular acne. Severe malformations have been documented in neonates whose mothers had taken isotretinoin during pregnancy. Women who became pregnant one cycle after completing therapy are believed to be at teratogenic risk not higher than baseline. We describe the case of a newborn whose mother had taken the drug for 4 weeks. The woman then had contraception for 4 weeks (after the drug treatment had finished), and became pregnant after that period. The newborn had isolated bilateral microtia due to suspected isotretinoin exposure. His mother also had a history of urine tract infection in the second week of pregnancy that was treated with cephalexin. The parents were not from a consanguineous marriage and had no family history of congenital malformations. To reduce the risk, effective contraception should be continued in fertile women more than 1 month after completing therapy.

Itch elicited by intradermal injection of serotonin, intracisternal injection of morphine, and their synergistic interactions in rats.

We used the cheek model of itch and pain in rats to determine the dose-response relationships for intradermal injection of serotonin and α methylserotonin on scratching behavior. We also determined the dose-related effects of intracisternally injected morphine on scratching, effects that were greatly reduced by administration of the opiate antagonist naloxone. We then examined the interactions of intradermal injection of serotonin and intracisternal injection of morphine on scratching and found that the two procedures act synergistically to increase itch. These results suggest that morphine applied to the CNS is capable of producing itch and greatly increasing itch originating in the skin (hyperknesis).

Uroguanylin induces electroencephalographic spikes in rats.

Uroguanylin (UGN) is an endogenous peptide that acts on membrane-bound guanylate cyclase receptors of intestinal and renal cells increasing cGMP production and regulating electrolyte and water epithelial transport. Recent research works demonstrate the expression of this peptide and its receptor in the central nervous system. The current work was undertaken in order to evaluate modifications of electroencephalographic spectra (EEG) in anesthetized Wistar rats, submitted to intracisternal infusion of uroguanylin (0.0125 nmoles/min or 0.04 nmoles/min). The current observations demonstrate that 0.0125 nmoles/min and 0.04 nmoles/min intracisternal infusion of UGN significantly enhances amplitude and frequency of sharp waves and evoked spikes (p = 0.03). No statistical significance was observed on absolute alpha and theta spectra amplitude. The present data suggest that UGN acts on bioelectrogenesis of cortical cells by inducing hypersynchronic firing of neurons. This effect is blocked by nedocromil, suggesting that UGN acts by increasing the activity of chloride channels.

Uroguanylin induces electroencephalographic spikes in rats / Uroguanilina induz potenciais em espiga no eletroencefalograma de ratos

Uroguanylin (UGN) is an endogenous peptide that acts on membrane-bound guanylate cyclase receptors of intestinal and renal cells increasing cGMP production and regulating electrolyte and water epithelial transport. Recent research works demonstrate the expression of this peptide and its receptor in the central nervous system. The current work was undertaken in order to evaluate modifications of electroencephalographic spectra (EEG) in anesthetized Wistar rats, submitted to intracisternal infusion of uroguanylin (0.0125 nmoles/min or 0.04 nmoles/min). The current observations demonstrate that 0.0125 nmoles/min and 0.04 nmoles/min intracisternal infusion of UGN significantly enhances amplitude and frequency of sharp waves and evoked spikes (p = 0.03). No statistical significance was observed on absolute alpha and theta spectra amplitude. The present data suggest that UGN acts on bioelectrogenesis of cortical cells by inducing hypersynchronic firing of neurons. This effect is blocked by nedocromil, suggesting that UGN acts by increasing the activity of chloride channels.

A uroguanilina (UGN) é um peptídeo endógeno que age em receptores do tipo guanilato ciclase de membrana de células intestinais e renais aumentando a produção de GMPc e regulando o transporte epitelial de eletrólitos e água. Pesquisas recentes demonstraram a expressão deste peptídeo e de seus receptores no sistema nervosa central. O presente trabalho foi realizado com objetivo de avaliar possíveis mudanças no espectro do eletroencefalograma (EEG) de ratos Wistar anestesiados, submetidos à infusão intracisternal de uroguanilina (0.0125 nmoles/min or 0.04 nmoles/min). Os resultados apresentados no corrente trabalho demonstram que a infusão intracisternal de ambas as doses de UGN aumenta significativamente a amplitude e frequência das espículas (p = 0.03). Não foram encontradas diferenças estatísticas na amplitude absoluta dos espectros alfa ou teta. Os dados apresentados neste trabalho mostram que a UGN age na bioeletrogênese de células corticais induzindo disparo hipersincrônico de neurônios. Este efeito é bloqueado por nedocromil, sugerindo que UGN atua pelo aumento de atividade de canais de cloreto.

Novel modified method for injection into the cerebrospinal fluid via the cerebellomedullary cistern in mice.

A modified method of injection into the cerebellomedullary (CM) cistern of mice was developed based on fixation of the mouse with a special mask under inhalation anesthesia, and exposure of the sagittal suture of the cranium and midline of the nape to allow us to visualize injection point directly. The accuracy of the modified method was evaluated using the temporal and spatial intracranial distribution of dye by intracisternal injection of 6- microliter methylene blue aqueous solution. A high concentration of dye was found in the CM cistern, the ventral cisterns, and intracranial proximal portion of the main cranial nerves at 1 hour after injection. The color of the dye in the CM cistern and the ventral cisterns was lighter, and the dye had reached the intracranial distal portion of the main cranial nerves at 6 hours after injection. The dye was completely eliminated by cerebrospinal fluid (CSF) circulation at 24 hours after injection. No severe brain injury was found in any of the 20 mice. Intracisternal injection was successful in all 14 mice sacrificed 1 hour or 6 hours after injection according to the confirmation of dye distribution. The effects of central administration of endothelin-1 (ET1) were evaluated on cerebral blood supply, constriction of cerebral arteries, and change of respiration in mice. Three doses of ET1 were studied: 2 micrograms (0.8 nmol), 4 micrograms (1.6 nmol), and 6 micrograms (2.4 nmol). Cerebral blood flow (CBF) was monitored for 60 minutes following injection using a laser Doppler probe. Intracisternal ET1 injection induced dose-dependent reduction of CBF, constriction of cerebral arteries, and respiratory depression in mice. This modified method of injection into the CM cistern under direct visualization provides accurate and reproducible injection into the CSF, and can be used to investigate the effects of various chemical substances on the central nervous system in mice.

Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia.

PURPOSE: Intractable neuropathic dynamic allodynia remains one of the major symptoms of human trigeminal neuropathy and is commonly accepted to be the most excruciatingly painful condition known to humankind. At present, a validated animal model of this disorder is necessary for efficient and effective development of novel drug treatments. Intracisternal strychnine in rats has been shown to result in localized trigeminal dynamic allodynia, thus representing a possible model of trigeminal neuralgia. The purpose of this study was to validate a mouse model of trigeminal glycinergic inhibitory dysfunction using established positive (carbamazepine epoxide) and negative (morphine) controls. METHODS: The actions of conventional first-line treatment (carbamazepine epoxide [CBZe]) and clinically ineffective morphine were tested for trigeminal dynamic mechanical allodynia produced by intracisternal strychnine. In mice under halothane anesthesia, we injected either strychnine (0.3 µg), strychnine with CBZe (4 ng), or artificial cerebrospinal fluid (aCSF) intracisternally (i.c.). In a separate set of experiments, subcutaneous morphine (3 mg·kg(-1) sc) was injected with intracisternal strychnine. Dynamic mechanical allodynia was induced by stroking the fur with polyethylene (PE-10) tubing. The response of each mouse was rated to determine its allodynia score, and scores of each group were compared. In addition, in a separate dichotomous disequilibrium study, pairs of mice were injected with strychnine/saline, strychnine/strychnine-CBZe, or strychnine/strychnine-morphine. A blinded observer recorded which mouse of each pair had the greater global pain behaviour. RESULTS: Strychnine (i.c.) produced higher quantitative allodynia scores in the trigeminal distribution (mean 81.5%; 95% confidence interval [CI] 76.4 to 86.6) vs the aCSF group (mean 11.3%; 95% CI 8.1 to 14.4) (P < 0.0001). Carbamazepine epoxide (i.c.) completely abolished allodynia when co-injected with strychnine (mean 83.2%; 95% CI 78.1 to 88.4) vs strychnine alone (mean 3.2%; 95% CI -0.9 to 7.2) (P < 0.0001). Morphine co-injected with strychnine did not result in reduced allodynia (mean 65.7%; 95% CI 42.0 to 89.4) compared with strychnine alone (mean 87.6%; 95% CI 77.6 to 97.6) (P = 0.16). In a further global allodynia assessment, strychnine (i.c.) produced greater allodynia than both aCSF and strychnine administered with CBZe (P = 0.03). Morphine (ip) administered with strychnine did not result in reduced global allodynia compared with strychnine administered alone (P = 1.0). CONCLUSION: In this study, we have developed and validated a novel murine model of trigeminal dynamic allodynia induced by intracisternal strychnine. The use of mice to study trigeminal allodynia has many benefits, including access to a vast repository of transgenic mouse variants, ease of handling, low cost, and minimal variance of results. The present model may have utility in screening drug treatments for dynamic mechanical allodynia resulting from trigeminal neuropathies.

Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation.

Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freund's adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Intra-cisterna magna anti-CX3CR1 or anti-interleukin (IL)-1ß neutralizing antibody administration decreased the enhanced excitability of Vc and C1-C2 neurons in CFA-injected rats, whereas intra-cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1ß expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1-C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2-C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1-C2 or C2-C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1ß is released from the activated microglia, and the excitability of neurons in Vc and C1-C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia.

Effects of intracisternal dexmedetomidine on cerebral neuronal cells in rat: a preliminary study.

AIM: The aim was to investigate whether dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route. MATERIAL AND METHODS: Eighteen rats were anesthetized and the right femoral artery was cannulated. Mean arterial pressures, heart rates, arterial carbon dioxide tension, arterial oxygen tension, and blood pH were recorded. When the free cerebrospinal fluid flow was seen, 0.1 ml normal saline (Group SIC, n=6) or 9 µg/kg diluted dexmedetomidine in 0.1 ml volume (Group DIC, n=6) was administered into the cisterna magna of rats. After 24 hours, the whole body blood was collected for measurement of plasma lipid peroxidation (LPO) levels. The hippocampal formations used for histopathological examination and measurement of tissue LPO levels. RESULTS: There was a statistically significant difference between the DIC/SIC groups and DIC/CONTROL groups regarding the brain LPO levels (p=0.002, p < 0.001, respectively). Plasma LPO levels were statistically different between the CONTROL/DIC groups, CONTROL/SIC groups, DIC/ SIC groups (p=0.002, p=0.047, p=0.025, respectively), The picnotic neuron counts were different between the CONTROL/SIC groups, CONTROL/ DIC groups, DIC/SIC groups (p < 0.001, p=0.001, p=0.024, respectively). CONCLUSION: In conclusion, dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route.

Matricellular protein: a new player in cerebral vasospasm following subarachnoid hemorrhage.

INTRODUCTION: Matricellular protein (MCP) is a class of nonstructural and secreted extracellular matrix proteins that exert diverse functions, but its role in vascular smooth muscle contraction has not been investigated. MATERIAL AND METHODS: First, rat subarachnoid hemorrhage (SAH) models were produced by endovascular perforation and examined for tenascin-C (TNC) and osteopontin (OPN) induction (representatives of MCPs) in vasospastic cerebral arteries using immunostaining. Second, recombinant TNC (r-TNC), recombinant OPN (r-OPN), or both were injected into a cisterna magna in healthy rats, and the effects on the diameter of basilar arteries were determined using India ink angiography. RESULTS: In SAH rats, TNC immunoreactivity was markedly induced in the smooth muscle cell layers of spastic cerebral arteries on day 1 but not in control animals. The TNC immunoreactivity decreased on day 3 as vasospasm improved: OPN immunoreactivity, on the other hand, was more induced in the arterial wall on day 3. r-TNC injections caused prolonged contractions of rat basilar arteries, which were reversed by r-OPN, although r-OPN itself had no effect on the vessel diameter. CONCLUSIONS: MCPs, including TNC and OPN, may contribute to the pathophysiology of cerebral vasospasm and provide a novel therapeutic approach against it.

Pressor response to L-cysteine injected into the cisterna magna of conscious rats involves recruitment of hypothalamic vasopressinergic neurons.

The sulfur-containing non-essential amino acid L-cysteine injected into the cisterna magna of adult conscious rats produces an increase in blood pressure. The present study examined if the pressor response to L-cysteine is stereospecific and involves recruitment of hypothalamic vasopressinergic neurons and medullary noradrenergic A1 neurons. Intracisternally injected D-cysteine produced no cardiovascular changes, while L-cysteine produced hypertension and tachycardia in freely moving rats, indicating the stereospecific hemodynamic actions of L-cysteine via the brain. The double labeling immunohistochemistry combined with c-Fos detection as a marker of neuronal activation revealed significantly higher numbers of c-Fos-positive vasopressinergic neurons both in the supraoptic and paraventricular nuclei and tyrosine hydroxylase containing medullary A1 neurons, of L-cysteine-injected rats than those injected with D-cysteine as iso-osmotic control. The results indicate that the cardiovascular responses to intracisternal injection of L-cysteine in the conscious rat are stereospecific and include recruitment of hypothalamic vasopressinergic neurons both in the supraoptic and paraventricular nuclei, as well as of medullary A1 neurons. The findings may suggest a potential function of L-cysteine as an extracellular signal such as neuromodulators in central regulation of blood pressure.

Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats.

To investigate the role of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in postoperative cognitive dysfunction (POCD) in aged rats, we used laparotomy to mimic human abdominal surgery in adult (3 months) and aged (24 months) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear-conditioning task is significantly impaired in aged but not young rats 4 d after surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1ß in the hippocampus of aged animals 1 and 4 d after surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline after a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112 µg) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral, IL-1ß in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 d) compared with in the blood (<24 h) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.

IL-1RA injected intra-cisterna magna confers extended prophylaxis against lipopolysaccharide-induced neuroinflammatory and sickness responses.

IL-1RA has been used intra-cerebrally to ameliorate neuroinflammatory responses. The present study explored the possibility that the bioactivity of IL-1RA administered intra-cerebrally may be prolonged in the CNS. hIL-1RA was detected in hippocampus from 2h to 14d post-ICM treatment. hIL-1RA ameliorated both the hippocampal cytokine (TNFα and NFκBIα) and sickness response to peripheral LPS administered 4d after hIL-1RA. Four days post treatment, hIL-1RA reduced the basal expression of IL-1R1, Iba-1, MHCII, and TLR4 and blunted the microglial IL-1ß and IL-6 response to LPS ex vivo. IL-1RA might be administered prophylactically to prevent the neuroinflammatory effects of trauma.

Participation of microglial p38 MAPK in formalin-induced temporomandibular joint nociception in rats.

AIMS: To investigate nociceptive behavior and the immunoreactivity of microglia and phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) following intracisternal administration of SB203580, a p38 MAPK inhibitor, or minocycline, a microglia inhibitor, in rats with temporomandibular joint (TMJ) inflammation. METHODS: The number of nociceptive behavioral responses was recorded for nine successive 5-minute intervals following formalin injections into the left TMJ. SB203580 or minocycline was administered intracisternally 2 hours prior to the formalin injection. Statistical analysis used one-way analysis of variance followed by least significant difference post-hoc analysis. RESULTS: The intra-articular injection of formalin increased the expression of p-p38 MAPK in the ipsilateral medullary dorsal horn. Most of the p-p38 MAPK co-localized with OX42, a microglial marker, but not with GFAP, an astrocyte marker. Intracisternal injections of SB203580 (0.5, 1, or 5 Μg) attenuated the number of nociceptive behavioral responses and the expression of p-p38 MAPK in the medullary dorsal horn. Intracisternal injections of minocycline (25 or 50 Μg) also attenuated the responses and the expression of OX42 and p-p38 MAPK in the medullary dorsal horn. CONCLUSION: These findings suggest that p38 MAPK in microglia plays an important role in the central processing of inflammatory TMJ nociception in rats. The data further indicate that a targeted blockade of the microglial p38 MAPK pathway is a potentially important new treatment strategy for inflammatory TMJ nociception.