John J. O'Connor

Actions of TNF‐α on glutamatergic synaptic transmission in the central nervous system

Increasing attention is being paid to the role of inflammatory and immune molecules in the modulation of central nervous system (CNS) function. Tumour necrosis factor‐α (TNF‐α) is a pro‐inflammatory cytokine, the receptors for which are expressed on neurones and glial cells throughout the CNS. Through the action of its two receptors, it has a broad range of actions on neurones which may be either neuroprotective or neurotoxic. It plays a facilitatory role in glutamate excitotoxicity, both directly and indirectly by inhibiting glial glutamate transporters on astrocytes. Additionally, TNF‐α has direct effects on glutamate transmission, for example increasing expression of AMPA receptors on synapses. TNF‐α also plays a role in synaptic plasticity, inhibiting long‐term potentiation (LTP), a process dependent on p38 mitogen activated kinase (p38 MAP) kinase. In the following review we look at these and other effects of TNF‐α in the CNS.

Clinical results of the Oxford knee. Surface arthroplasty of the tibiofemoral joint with a meniscal bearing prosthesis.

The Oxford method of knee arthroplasty replaces the femoral condyles with convex spherical metal components and relines the tibial plateaus with flat metal components. Free meniscal bearings of polyethylene, spherically concave above and flat below, lie between the fixed metal components, held in place by their geometry and ligamentous tension. Advantages of the design include: congruity of the articulating surfaces; unconstrained tibiofemoral movement; preservation of all the ligaments with facility to tension them accurately from a range of bearing thicknesses; minimal bone excision; applicability to unicondylar use. Laboratory studies showed that combined rolling and sliding at meniscofemoral and meniscotibial interfaces mimic normal joint kinematics and mechanics. One hundred twenty-five bicompartmental implants were followed for two to six years. Pain was relieved in 90%; mean flexion limit was 99 degrees and mean flexion deformity 7 degrees. Stability and alignment were recovered in nearly all joints. Six knees failed and were successfully arthrodesed (two) or converted to another prosthesis (four). Eight knees required revision to replace a dislocated bearing (five) or to recement a loose component (three). In knees with an intact anterior cruciate ligament, there were no failures and a low revision rate (4.8%). The prosthesis is proposed as a reliable and safe alternative to more invasive prostheses in rheumatoid and osteoarthritic joints in which the disease is still limited to the articular surfaces.

Dissection of tumor-necrosis factor-α inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early—but not late—phase LTP

The pro-inflammatory cytokine tumor-necrosis factor-alpha (TNF-alpha) is elevated in several neuropathological states that are associated with learning and memory deficits. Previous work has reported that TNF-alpha inhibits the induction of LTP in areas CA1 [Neurosci Lett 146 (1992) 176] and dentate gyrus [Neurosci Lett 203 (1996) 17]. The mechanism(s) underlying this process of inhibition have not to date been addressed. Here, we show that perfusion of TNF-alpha prior to long-term potentiation (LTP) inducing stimuli inhibited LTP, and that in late-LTP (3 h post-tetanus) a depression in synaptic field recordings was observed (68 +/- 5%, n = 6 versus control 175 +/- 7%, n = 6, P < 0.001). We investigated the involvement of the mitogen-activated protein kinase (MAPK) p38 in the inhibition of LTP by TNF-alpha as p38 MAPK has previously been shown to be involved in interleukin-1beta inhibition of LTP in the dentate gyrus [Neuroscience 93 (1999b) 57]. Perfusion of TNF-alpha led to an increase in the levels of phosphorylated p38 MAPK detectable in the granule cells of the dentate gyrus. The p38 MAPK inhibitor SB 203580 (1 microM) was found by itself to have no significant effect on either early or late phase LTP in the dentate gyrus. SB 203580 was found to significantly reverse the inhibition of early LTP by TNF-alpha (SB/TNF-alpha 174 +/- 5%, n = 6 versus TNF-alpha 120 +/- 7%, n = 6, P < 0.001, 1 h post-tetanus) to values comparable to control LTP (control 175 +/- 7%, n = 6). Interestingly however, the depressive effects of TNF-alpha on late LTP (2-3 h) were clearly not attenuated by p38 MAPK inhibition (SB/TNF-alpha 132 +/- 5%, n = 6 versus control LTP 175 +/- 7%, n = 6, P < 0.001, 3 h post-tetanus). This work suggests that TNF-alpha inhibition of LTP represents a biphasic response, a p38 MAPK-dependent phase that coincides with the early phase of LTP and a p38 MAPK independent phase that temporally maps to late LTP.

THE RELATIONSHIP BETWEEN DEGENERATIVE CHANGES AND LOAD-BEARING IN THE HUMAN HIP

1. A predictable pattern of degeneration occurs on both the femoral head and the acetabulum and this pattern is age dependent. 2. The degenerative areas on the femoral head are related to habitual non-use. 3. The hip is shown to be anatomically incongruent, and the dome of the acetabulum, a predictable area of degeneration, is shown also to be an area of habitual non-use. 4. The possible relationships between age-dependent degenerative changes and senile degenerative joint disease is discussed and the importance of changing geometry stressed.

The anterior cruciate ligament in knee arthroplasty : a risk-factor with unconstrained meniscal prostheses

Three hundred one unconstrained meniscal arthroplasties were observed for as long as nine years, during which time 25 (8.3%) failed. Risk factors were sought by comparing the distributions of several preoperative variables in the group that failed with the group that was successful. Age, weight, the magnitude or direction of preoperative deformity, and the presence of postoperative malalignment were all without effect on the outcome of the operations. Knees with rheumatoid arthritis had a 95% survival rate at six years. Knees with osteoarthrosis had an equivalent survival rate of 83%. Knees in which the anterior cruciate ligament (ACL) was normal had a survival rate of 95% at six years; those in which the ligament was damaged or absent had an equivalent survival rate of 81%. Successful reconstruction of a knee with an unconstrained meniscal implant requires the presence and the preservation of an intact ACL.

Actions of the Pro-Inflammatory Cytokine Il-1[beta] on Central Synaptic Transmission

Within the last decade huge advances have been made in the understanding of the interactions between the central nervous system (CNS) and the immune system. Foremost amongst these is the realization that cytokines, classically regarded as mediators and co‐ordinators of the inflammatory and immune responses, can exert a number of neuromodulatory effects within the CNS under both physiological and pathological conditions (for recent reviews see Rothwell & Hopkins, 1995; Rothwell et al. 1997; Rothwell, 1999). Consistent with this, it has been shown that many cytokines and their receptors are present in the brain (Hopkins & Rothwell, 1995). Much attention has focused on the pro‐inflammatory cytokine interleukin‐1 (IL‐1) especially the [beta] variant. IL‐1[beta] has been shown to be produced in the CNS in response to a number of stimuli including peripheral administration of lipopolysaccharide (LPS); traumatic brain injury; acute stress; anorexia and [beta]‐adrenoceptor agonist administration (e.g. Maruta et al. 1997). IL‐1 receptors have also been shown to be present in many brain regions, with high levels in the hippocampus and hypothalamus (Ban et al. 1991). Expression of IL‐1 receptors has also been shown to be upregulated in response to insult, e.g. kainic acid administration (Nishiyori et al. 1997) and expression is higher in aged animals (Murray & Lynch, 1998). However this review will concentrate on the effects of IL‐1[beta] on hippocampal synaptic transmission and long‐term potentiation (LTP), a process long thought to be an important underlying mechanism of learning and memory formation (for review see Bliss & Collingridge, 1993).

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-alpha, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-alpha have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-alpha on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-alpha is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-alpha is now known to cause transient increases in intracellular Ca(2+) levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca(2+) homeostasis could be involved. Ryanodine was found to significantly reverse the inhibition of LTP by TNF-alpha. From these studies we propose that the TNF-alpha inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca(2+) stores in TNF-alpha mediated inhibition of LTP.

Fast cyclic voltammetry can be used to measure stimulated endogenous 5-hydroxytryptamine release in untreated rat brain slices

Fast cyclic voltammetry at a carbon fibre microelectrode was used to monitor the time course of 5-hydroxytryptamine (5-HT) overflow in slices of rat dorsal raphe (DRN) and suprachiasmatic nuclei (SCN), incubated in a brain slice chamber for over 6 h. 5-HT overflow was detected in response to electrical brain stimulation in both regions. Voltammetric evidence showed that the released substance was identical to exogenously applied 5-HT. Overflow was reversibly abolished when Ca2+ was removed from the incubating medium or when TTX was added. Ro4-1284, a reserpine like agent, irreversibly abolished 5-HT overflow from both nuclei. The 5-HT uptake blockers, citalopram, clomipramine, fenfluramine and fluvoxamine dose dependently increased overflow and slowed the rate of removal of 5-HT from the extracellular space in both regions. Benztropine had no effect on overflow in the DRN and SCN whereas it caused a significant increase in dopamine overflow in slices of caudate putamen (CPu). Xylamine had no effect on 5-HT overflow in the DRN and SCN. This evidence indicates that the release of endogenous 5-HT can be measured reliably for long periods and that FCV can be used in brain slices for quantitative studies of 5-HT release and uptake.

Co-abuse of opiates and benzodiazepines

The objective of the study was to assess what differences exist between individuals who are dependent on opiates and benzodiazepines and compare to those who are dependent on opiates. A questionnaire was compiled and administered to patients who had been consecutively admitted to an inpatient drug treatment unit. The prevalence of benzodiazepine dependency was 54 per cent [n=34]. Patients dependent on benzodiazepines and opiates were significantly older, had been admitted for methadone stabilisation and were more likely to have been prescribed a methadone maintenance programme prior to admission. They had used heroin longer, benzodiazepines more frequently, at larger doses for a longer duration of time and tended to use more drugs in general. They were found to be more psychologically vulnerable than those not dependent on benzodiazepines as they were significantly more likely to have described a past experience of depression and a past episode of deliberate self harm.

Pharmacological characteristics of 5‐hydroxytryptamine autoreceptors in rat brain slices incorporating the dorsal raphe or the suprachiasmatic nucleus

1 Changes in extracellular concentrations of 5‐hydroxytryptamine elicited by electrical stimulation in rat brain slices containing the dorsal raphe nucleus and the suprachiasmatic nucleus were monitored with fast cyclic voltammetry. 2 Using pseudo single pulse stimulation (5 pulses applied at 100 Hz) we have shown that the release of 5‐hydroxytryptamine in the dorsal raphe and the suprachiasmatic nucleus can be regulated by autoreceptors in both brain regions. 3 In the suprachiasmatic nucleus, 5‐carboxamidotryptamine, RU24969, 1‐(m‐trifluoromethylphenyl) piperazine and sumatriptan caused a concentration‐dependent inhibition of stimulated 5‐hydroxytryptamine overflow in the range 1 × 10−9 m to 3 × 10−6 m. The actions of 5‐carboxamidotryptamine and RU24969 were reversed competitively by methiothepin (10−8 m to 10−6 m); Schild plots revealed pKB values of 7.9 and 8.1. By contrast, ipsaparone and 8‐hydroxy‐2(di‐n‐propylamino)tetralin (8‐OH‐DPAT) are not effective 5‐hydroxytryptamine autoreceptor agonists in the suprachiasmatic nucleus. 4 Isamoltane (10−6 m), the putative 5‐HT1B receptor antagonist, blocked the responses to RU24969 (10−6 m) and 1‐(m‐trifluoromethylphenyl)piperazine (10−6 m) in the suprachiasmatic nucleus. 5 In the dorsal raphe nucleus, 8‐OH‐DPAT, ipsapirone, RU24969, 5‐carboxamidotryptamine, and sumatriptan (all 1×10−8 m to 3×10−6 m) produced a concentration‐dependent reduction in the stimulated release of 5‐hydroxytryptamine. The maximum effect observed was less than that seen in the suprachiasmatic nucleus. 6 Methiothepin (1 × 10−7 m) blocked the effect of 5‐carboxyamidotryptamine (10−8 m to 10−6 m) in the dorsal raphe nucleus while propranolol (10−6 m) and NAN‐190 (10−6 m) but not isamoltane (10−6 m) were found to block significantly the effect of ipsapirone (10−6 m). 7 We conclude, that drugs with 5‐HT1A binding activity act as agonists in the dorsal raphe nucleus while drugs showing some activity for 5‐HT1B and 5‐HT1D binding sites, act as agonists in the suprachiasmatic nucleus. Our results confirm predictions from binding studies, that functional 5‐HT autoreceptors regulating release of endogenous 5‐HT have different drug specificity in the dorsal raphe and suprachiasmatic nucleus.