Brain Advance Access originally published online on June 4, 2003
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Brain, Vol. 126, No. 7, 1683-1690,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg160
Clinical and neuroinflammatory responses to meningoencephalitis in substance P receptor knockout mice
1 Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, 2 Department of Veterinary Clinical Studies, University of Glasgow, Glasgow, 3 Department of Anatomy and Developmental Biology, University College London, London, 4 Department of Statistics and Modelling Science, University of Strathclyde, Glasgow, 5 Department of Pharmacology, Boston University School of Medicine, Boston, MA, USA and 6 Instituto de Neurociencias, Universidad Miguel Hernández, San Juan, Alicante, Spain
Correspondence to: Professor Peter G. E. Kennedy, Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK E-mail: P.G.Kennedy{at}clinmed.gla.ac.uk
Received December 13, 2002. Revised February 24, 2003. Accepted February 24, 2003.
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Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1–/– mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1–/– mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1–/– mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1–/– mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.
Keywords: brain; meningoencephalitis; mice; substance P; trypanosomiasis
Abbreviations: GFAP = glial fibrillary acidic protein; HAT = human african trypanosomiasis; i.p. = intraperitoneal; PTRE = post-treatment reactive encephalopathy; SP = substance P
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Introduction |
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Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by the parasites Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense. The disease is invariably fatal if untreated, and in the late stage of the infection there is CNS involvement. The latter includes a wide variety of neurological features including sleep disturbances, abnormalities of cognition and mood, motor system involvement, sensory disturbances, cerebral oedema and finally coma (de Atouguia and Kennedy, 2000
). Unfortunately, use of the arsenical derivative melarsoprol, the drug of choice for treatment of this stage of the disease, is associated with the development of a severe post-treatment reactive encephalopathy (PTRE), in which the typical clinical and neuroinflammatory features of late-stage HAT are greatly exacerbated (de Atouguia and Kennedy, 2000). This severe adverse reaction can occur in up to 10% of cases, and may be fatal (Adams et al., 1986; Pepin and Milord, 1991). The CNS lesions in both late-stage disease and PTRE show a number of characteristic inflammatory features, which include perivascular cuffing with the presence of lymphocytes, macrophages and plasma cells in the context of a severe meningoencephalitis (Adams and Graham, 1998). Although the neuropathogenesis of the PTRE is unknown, current evidence strongly implicates the role of immunological mechanisms within the CNS and the involvement of several cytokines (Hunter and Kennedy, 1992). Early astrocyte activation also appears to be significant in initiating the inflammatory process in PTRE (Hunter et al., 1992).
Over the last decade we have studied PTRE in a murine model of Trypanosoma brucei brucei infection that shows remarkable pathological similarities to those seen in the CNS of individuals with sleeping sickness (Kennedy, 1999). Intraperitoneal (i.p.) inoculation of mice with cloned stabilates of T. b. brucei produces a chronic parasite infection with parasites present in the CNS by day 21 post-infection, and the characteristic histological changes become evident within the CNS during the later stages of the infection, analogous to the human disease. This inflammatory response can be exacerbated reproducibly by treating the mice subcuratively with trypanocidal drugs, such as diminazene aceturate (Berenil®), which clear the parasites from the extravascular compartment but not the CNS (Jennings and Gray, 1983). This results in a condition that closely mimics the PTRE characteristics of human subjects. The mouse model has proved invaluable in studies of both the neuropathogenesis of PTRE and the experimental modulation of this condition with drugs such as azathioprine (Gichuki et al., 1997) and eflornithine (Jennings et al., 1997).
Recent investigations in our laboratory have strongly implicated a key role for the neuropeptide substance P (SP) in the generation of the inflammatory response seen in this mouse model of PTRE (Kennedy et al., 1997). SP is an 11 amino acid neuropeptide that has widespread distribution and function within the CNS and peripheral systems. This includes elaboration of immunological mechanisms with effects on both T and B cell function (McGillis et al., 1987) and the stimulation of a variety of cytokines including interleukin-1, interleukin-6 and tumour necrosis factor 
(Wagner et al., 1987; Lotz et al., 1988; Lee et al., 1994), all of which are known to be implicated in PTRE (Hunter et al., 1992). SP exerts its diverse effects by activating the tachykinin NK1 receptor, which is widely expressed by particular neuronal populations in the CNS and in peripheral systems (Quartara and Maggi, 1998). Administration of the non-peptide, SP antagonist RP-67,580, which binds specifically to NK1 receptors, consistently produced moderate but significant amelioration of the meningoencephalitis associated with PTRE induced in trypanosome-infected mice (Kennedy et al., 1997). The mechanism of action of SP in this reaction as yet remains unclear. Therefore, in order to gain further insight into the role of SP in immune-mediated neuroinflammatory conditions, with the long-term goal of devising novel therapeutic strategies in patients, we induced the PTRE in mice that could not express this NK1 receptor due to disruption of exon 1 of the gene encoding the receptor.
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Material and methods |
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Animals and infections
C57BL/6 mice in which the NK1 receptor had been disrupted (NK1–/–) were used. These mice are known to breed homozygously and are phenotypically normal (de Felipe et al., 1998
). C57BL/6 mice derived from the breeding colony employed in the production of these NK1–/– animals were used as NK1+/+ controls. Groups of NK1+/+ (wild type) and NK1–/– (knockout) mice were infected with 3 x 104 parasites of T. b. brucei (cloned stabilate GVR 35/C1.6) by i.p. injection. In experiment 1, the infected animals were treated with diminazene aceturate (40 mg/kg i.p.) on day 28 post-infection. This produced an acute reaction resulting in the death of several mice. To reduce the severity of this response, in experiments 2 and 3 the diminazene aceturate treatment was administered at day 21 post-infection. Over many years’ experience of this model, the dosage of diminazene aceturate has been optimized to induce consistent neuroinflammatory changes, thereby allowing single dose rates to be applied. Control groups including uninfected knockout and wild-type mice, treated in an identical manner to the infected mice, were incorporated into the experimental design. All mice were killed 40 days following infection. This work was performed under the authority of Home Office licensing regulations.
Preparation of antagonists
NK2 (SR 48968) and the NK3 (SR 142801) receptor antagonists (Sanofi Recherche, Montpellier, France) were dissolved in 0.5 ml of dimethyl sulphoxide and diluted to 250 µg/ml with 0.9% sterile saline. A combined solution containing 250 µg/ml NK2 receptor antagonist and 250 µg/ml NK3 receptor antagonist was also prepared.
Antagonist experiments
In experiment 4, groups of NK1 receptor wild-type and knockout mice were administered 25 µg of NK2 receptor antagonist, 25 µg NK3 receptor antagonist, or a combination of 25 µg of NK2 and 25 µg NK3 receptor antagonists (i.p.) 3 days prior to trypanosome infection and daily until they were killed at day 40 post-infection. The animals were treated on day 21 post-infection with diminazene aceturate. Control groups of mice including; infected knockout and wild-type mice given no antagonist treatment and uninfected knockout and wild-type animals treated with a combination of the NK2 and NK3 receptor were included in the experimental design. All control groups of mice received diminazene aceturate treatment on day 21 post-infection.
Clinical assessment
Throughout the experiment each animal was examined to determine the degree of clinical impairment using a visual assessment scale. In this scale, 0 indicated healthy animals; grade 1 animals appeared slow and sluggish with a staring coat; animals showing reduced coordination of the hind limbs and altered gait were assigned a grade of 2; mice developing a flaccid paralysis of one hind limb were graded as 3; while those showing atrophy of the muscles and hind quarters, with flaccid paralysis of both hind limbs were considered a grade 4. Moribund mice were classed as grade 5, and a grade 6 score indicated death or euthanasia due to the severity of the condition.
Neuroinflammatory assessment
At necropsy the brains were removed, fixed in neutral buffered formalin and embedded in paraffin wax (Kennedy et al., 1997). Haematoxylin and eosin-stained sections were examined and the degree of neuropathological change was determined independently by two assessors, in a blinded fashion using pre-defined injury scores (Kennedy et al., 1997). In this system a score of 0 was assigned to sections showing a normal histopathology with no infiltration of inflammatory cells. Sections showing a mild meningitis with a few inflammatory cells in the meninges but no perivascular cuffing were graded as 1, while those with a moderate meningitis and cuffing of some of the vessels were assigned grade 2. The severity of the meningitis increased further and perivascular cuffs became prominent with mild infiltration of the neuropil by some inflammatory cells these sections were assigned a neuropathology score of 3. A grading score of 4 was reserved for sections displaying severe meningitis, prominent perivascular cuffs and a severe encephalitis with the presence of many inflammatory cells in the neuropil.
Immunocytochemistry
Astrocyte activation was assessed using indirect immunocytochemistry to stain for glial fibrillary acidic protein (GFAP) (Kennedy et al., 1997). In a sample of eight NK1–/– and eight NK1+/+ animals taken from experiments 1 and 2, the intensity and extent of GFAP staining, the complexity of the astrocytic processes and the number of astrocytes present were considered (Kennedy et al., 1997).
Statistical analyses
Comparisons of clinical appearance and neuroinflammatory responses between and amongst NK1–/– and NK1+/+ groups of mice were undertaken using two-sample unequal variance t-tests and the general linear model (GLM) routine for a randomized block design. Comparisons for groups of wild-type and knockout mice receiving combinations of NK2 receptor antagonist and NK3 receptor antagonist were undertaken using a factorial GLM design. The presence of significant interactions required separate analyses for wild-type and knockout mice using one-factor ANOVA (analysis of variance). Significant differences at the 5% level were investigated using Tukey’s multiple range test. In addition, comparisons between wild-type and knockout groups of mice receiving the same treatment were undertaken using the two-sample unequal variance t-test. Tests were carried out using a proprietary statistical software package and P values of <0.05 were considered significant. Means, SEs and P values are reported as summary statistics.
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Results |
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Clinical response in infected NK1 knockout mice
In the first series of experiments we determined the clinical and neuroinflammatory phenotype following experimental induction of the PTRE in NK1+/+ (wild-type) compared with NK1–/– (knockout) C57BL/6 mice. The extent of the histopathological response was assessed using an injury score as described previously (Kennedy et al., 1997
), and the extent of clinical involvement was determined using a grading scale that we developed for this study. Since the NK1–/– mice were lacking a functional NK1 receptor, we predicted that they would be both clinically and neuropathologically improved compared with the wild-type mice. The results of these experiments are summarized in Table 1. It can be seen that the severity of the clinical impairment for both NK1+/+ and NK1–/– mice following induction of PTRE was much greater in experiment 1 compared with experiments 2 and 3. This increase in the severity of the response reflects the later timing of the diminazene aceturate treatment in experiment 1. Analysis of the results in experiments 2 and 3 (P = 0.047), as well as the pooled data from all three experiments (P = 0.023), demonstrate that the degree of clinical impairment was significantly less in the NK1–/– mice compared with the NK1+/+ animals. Thus, disrupting the gene coding for the NK1 receptor in these mice was associated with a significantly reduced level of clinical impairment following induction of PTRE compared with wild-type mice of the same genetic background. This observation reinforces the putative role of SP in generating the PTRE in wild-type mice (Kennedy et al., 1997).
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Neuroinflammatory response in infected NK1 knockout mice
We expected the NK1–/– mice to show a corresponding improvement in the neuropathological injury score compared with wild-type mice, but the results were very different (Table 2). Histological examination of the brains in both groups of mice showed the characteristic inflammatory changes of PTRE with a moderate to severe meningitis, prominent perivascular cuffing and a moderate to severe encephalitis. The inflammatory cells within the lesions consisted of macrophages, lymphocytes and plasma cells in both the wild-type and NK1 knockout animals. The neuroinflammatory grades from experiment 1, experiments 2 and 3 together, and all three experiments combined were analysed. Each of these statistical analyses showed that the severity of the meningoencephalitic response was significantly greater in the NK1–/– mice compared with the NK1+/+ mice, with P values of 0.019, 0.003 and <0.001, respectively. Thus disrupting the gene coding for the NK1 receptor resulted in an increase rather than a decrease in the severity of the neuroinflammatory response compared with the wild-type mice following the induction of PTRE. When the number of astrocytes was analysed it was found that astrocyte counts were not significantly different (P = 0.699) between NK1+/+ mice (mean ± SE, 103.38 ± 4.47) and NK1–/– mice (106.32 ± 5.62), and there was no difference between the morphological appearance of the astrocytes in the two groups of mice. When we applied the same clinical and neuroinflammatory analyses to uninfected control mice (NK1–/– and NK1+/+) that had been treated with diminazene aceturate alone to exclude an independent effect of this drug irrespective of trypanosome infection, no clinical or neuroinflammatory abnormalities were detected in any of the experiments (data not shown).
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Effect of NK2 and NK3 receptor antagonists on the clinical and neuroinflammatory responses in infected NK1 knockout and wild-type mice
These results established that the NK1–/– mice demonstrated a disease phenotype in which the clinical response was significantly dissociated from the neuroinflammatory response. We next sought to determine the mechanism of this dissociation. Following induction of PTRE the role of SP may be taken over by other inflammatory mediators. The dissociation could also reflect alternative tachykinin receptor pathways. To pursue the latter possibility we carried out a series of experiments in which the NK2 and NK3 receptors in the NK1–/– mice were blocked by NK receptor antagonists prior to infection. Infected NK1–/– mice treated with a combination of NK2 and NK3 receptor antagonists showed a significantly reduced neuropathology score (P = 0.035) compared with infected NK1–/– mice that had not been treated with antagonists (Table 3, Fig. 1). This showed that the pathological response to infection had been mediated, at least in part, by NK2 or NK3 receptors. Treatment of the NK1–/– mice with either NK2 or NK3 receptor antagonists alone reduced the level of neuropathology compared with non-treated mice, but not significantly. Thus, there was a synergic effect of the two antagonists. Treatment of the infected NK1–/– mice with any of the receptor antagonist regimens had no significant effect on the clinical response compared with NK1–/– mice that had not received the antagonists (data not shown). This indicated that alternative tachykinin receptor usage was not relevant in the clinical response in NK1–/– mice.
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These results raised the possibility that NK2 and/or NK3 receptor usage may be important in wild-type mice. We also carried out the same series of NK receptor antagonist treatments in infected NK1+/+ mice, and obtained the results shown in Table 4. While none of the antagonist regimens reduced the pathology scores significantly compared with mice that had received no antagonists, we found that treatment with both the NK2 receptor antagonist alone and the NK2 and NK3 receptor antagonist combination was associated with a significantly increased neuroinflammatory score compared with treatment with NK3 receptor antagonist alone (P = 0.0495 and 0.006, respectively; Fig. 1). These findings suggest that in the wild-type mice the main NK2 ligand normally used by neurokinin A may be anti-inflammatory. As previously seen in the knockout mice, the clinical responses were not altered by antagonist treatments in the NK1+/+ mice. We also determined whether the clinical and neuroinflammatory responses differed significantly in the infected treated wild-type compared with the knockout mice. We found that the only significant difference in the clinical responses was obtained with the combined NK2 and NK3 receptor antagonists where the clinical scores were improved in the NK1–/– compared with the NK1+/+ mice (P = 0.024). Both the NK2 and the combined NK2 and NK3 receptor antagonist treatments produced significantly reduced neuroinflammatory scores in the NK1–/– compared with similarly treated NK1+/+ mice (P = 0.016 and 0.002, respectively).
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Discussion |
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Our data show that disrupting the gene coding for the NK1 receptor in mice results in a significant reduction in the clinical features associated with trypanosome-induced PTRE. This finding provides further compelling evidence for the role of SP in PTRE. It was, however, an intriguing and unexpected finding that this clinical improvement was not associated with an amelioration of the neuroinflammatory response or the degree of astrocyte activation seen in these mice. Indeed, the histopathological changes were more severe in the NK1–/– mice. While it seems very reasonable to assume that the increased inflammatory reaction in the NK1–/– mice is deleterious, it is not possible to completely exclude the possibility that in the NK1 knockout mice this reaction may be in part ‘beneficial’ to the host. This scenario of ‘beneficial’ CNS inflammation has previously been suggested in experiments involving aspirin treatment of T. b. brucei-infected rats. The infected animals given aspirin showed a reduction in the level of CNS inflammation; however, this amelioration of the inflammatory response was accompanied by an exacerbation of the neurodegenerative response (Quan et al., 2000
)
In contrast to the findings of the current study, our previous investigations using a non-peptide SP antagonist and CD-1 mice had shown a significant reduction in the meningoencephalitic and astrocytic response in mice treated with the antagonist (Kennedy et al., 1997). These antagonist-treated animals also showed a slightly reduced degree of hind limb paralysis (P.G.E. Kennedy, J. Rodgers and M. Murray, unpublished observations). Therefore, in the current study both the clinical and neuroinflammatory features were closely monitored and analysed using formal statistical protocols. Regarding genetic influences on the phenotype of PTRE, the difference between the two mouse strains employed in these studies is unlikely to be of major relevance, since both CD-1 and C57BL/6 mice are susceptible to the development of a PTRE. Moreover, the clinical and histopathological features of the latter are very similar in these two strains.
The use of the knockout NK1 receptor model allowed us to show that the clinical and neuroinflammatory responses to trypanosome infection were dissociated and were mediated by different pathways. Since SP binds preferentially to the NK1 receptor, extrapolation from previous data using an NK1 receptor antagonist (Kennedy et al., 1997) would have predicted a CNS neuroinflammatory improvement in the NK1–/– mice. The results with the NK2 and NK3 receptor antagonists in the NK1–/– mice clearly demonstrated that the remarkable neuroinflammatory exacerbation seen in these mice was due, in large part, to NK2 and NK3 receptor pathways. The expression of SP mRNA is known to be up-regulated in the NK1–/– mice (de Felipe et al., 1997). It is possible that in the NK1–/– mice, up-regulated tachykinins utilize NK2 and NK3 receptors in the absence of NK1 receptors causing a paradoxical exacerbation of the CNS neuropathology. Of relevance to this clinical/pathological dissociation is the recently described dissociation between different pathways mediating physiological parameters in these particular NK1 knockout mice (de Felipe et al., 1998; Murtra et al., 2000). In the latter studies of nociception and analgesia in NK–/– mice, it was found that the generation of stress-induced analgesia by SP was pharmacologically distinct from the opiate-mediated pathway.
The clinical/neuroinflammatory dissociation described in this experimental model is also a recognized feature of certain CNS diseases in humans, in particular, HIV encephalitis, in which patients with relatively mild clinical neurological involvement during life may show an unexpectedly severe degree of CNS pathology, and vice versa (Kennedy, 1993). A relative lack of clinical/pathological correlation is also sometimes seen in multiple sclerosis (Prineas and McDonald, 1997), although clearly this may also reflect the relative functional importance of the sites affected by the disease process. In this context it is significant that SP is increasingly recognized as being an important determinant in several types of neuroinflammatory diseases. This is reflected not only in generation of PTRE itself, but the ability of SP to induce HIV replication in vitro (Ho et al., 1996), the up-regulation of SP receptors located around lesions in the CNS (Mantyh et al., 1989) and the demonstration that sera from patients with falciparum malaria can induce SP gene expression in cultured brain microvascular endothelial cells (Chiwakata et al., 1996). It is possible that similar mechanisms, in which apparently independent pathways mediate the clinical and neuropathogenic responses, may operate in these diseases. Our results also strongly suggest that blocking such specific neuropeptide pathways, e.g. that mediated by the NK1 receptor, in CNS diseases involving neurokinin ligands may offer a novel therapeutic approach that could be a useful adjunct to conventional therapy. Thus in the case of CNS sleeping sickness we suggest further investigation of therapeutic regimes in which the PTRE may be prevented or modulated by a combination of a drug or drugs to kill the parasite and targeted anti-inflammatory therapy, such as a human non-peptide antagonist to the NK1 receptor.
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Acknowledgements |
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We would like to thank The Sir Jules Thorn Charitable Trust (grant reference no. 97/25A), and The Wellcome Trust for financial support of this research.
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