Compartmental changes in expression of c-Fos and FosB proteins in intact and dopamine-depleted striatum after chronic apomorphine treatment

Chronic administration of dopaminergic agonists to rats with unilateral 6-OH-dopamine (6-OHDA) lesions of nigrostriatal pathway produces behavioral sensitization to subsequent agonist challenges and may serve as a model for DOPA-induced dyskinesias. In order to understand striatal mechanisms behind this long-term behavioral change we examined striatal c-Fos and FosB immunoreactivity induced by apomorphine challenge (5 mg/kg, s.c.) after 3 days of withdrawal following a 2-week administration (5 mg/kg, b.i.d., s.c.) both in intact and 6-OHDA-lesioned animals. In intact rats, c-Fos induction by acute apomorphine exposure showed a striosomal pattern, whereas FosB immunopositivity was diffusely distributed. Following chronic administration, FosB induction turned to a clear striosome dominant pattern similar to c-Fos expression. In denervated striatum, expression of both proteins was profoundly augmented in a homogeneous pattern after a single dose of apomorphine. A distinct striosomal patterning appeared after chronic apomorphine administration in ventromedial part of the denervated striatum with a down-regulation in the matrix and relative enhancement in striosomes. These results suggest that compartmental reorganization of striatal neuronal activity may play a role in long-term behavioral changes induced by chronic dopaminergic treatments both under normal and dopamine-depleted conditions.     

Apoptosis in brain biopsies of subacute sclerosing panencephalitis patients

Subacute sclerosing panencephalitis (SSPE) is associated with inflammatory infiltration, neuronal loss, and demyelination. The pathogenesis of these changes is unclear. We examined DNA fragmentation and Bcl-2 expression in brain biopsies of nineteen SSPE patients to investigate the role of apoptosis in tissue damage. DNA fragmentation was present in oligodendroglia, and, in tissues with neuronal loss, in neurons. Reactive astrocytes had no DNA fragmentation, but strong Bcl-2 expression. These results suggest apoptosis as one of the mechanisms for oligodendroglial and neuronal death in SSPE.     

Is the Cell Death in Mesial Temporal Sclerosis Apoptotic?

PURPOSE: Mesial temporal sclerosis (MTS) is characterized by neuronal loss in the hippocampus. Studies on experimental models and patients with intractable epilepsy suggest that apoptosis may be involved in neuronal death induced by recurrent seizures. METHODS: We searched evidence for apoptotic cell death in temporal lobes resected from drug-resistant epilepsy patients with MTS by using the terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP (TUNEL) method and immunohistochemistry for Bcl-2, Bax, and caspase-cleaved actin fragment, fractin. The temporal lobe specimens were obtained from 15 patients (six women and nine men; mean age, 29 +/- 8 years). RESULTS: Unlike that in normal adult brain, we observed Bcl-2 immunoreactivity in some of the remaining neurons dispersed throughout the hippocampus proper as well as in most of the reactive astroglia. Bax immunopositivity was increased in almost all neurons. Fractin immunostaining, an indicator of caspase activity, was detected in approximately 10% of these neurons. Despite increased Bax expression and activation of caspases, we could not find evidence for DNA fragmentation by TUNEL staining. We also could not detect typical apoptotic changes in nuclear morphology by Hoechst-33258 or hematoxylin counterstaining. CONCLUSIONS: These data suggest that either apoptosis is not involved in cell loss in MTS, or a very slow rate of cell demise may have precluded detecting TUNEL-positive neurons dying through apoptosis. Increased Bax expression and activation of caspases support the latter possibility.     

Altered mechanisms of motor-evoked potential generation after transient focal cerebral ischemia in the rat: implications for transcranial magnetic stimulation

We recently demonstrated that a long-lasting transmission defect in cortical synapses caused motor dysfunction after brief middle cerebral artery (MCA) occlusion in the rat despite rapid recovery of axons. In this experimental study, we have examined the impact of differential recovery of synapses and axons on generation of motor-evoked potentials (MEP) recorded from contralateral paralyzed and ipsilateral unaffected muscles, to gain insight into mechanisms of MEPs recorded from stroke patients by transcranial magnetic stimulation (TMS). MEPs generated by focal electrical stimulation of the forelimb area of motor cortex were simultaneously recorded from the brain stem, contra- and ipsilateral forelimb and contralateral hindlimb muscles in rats subjected to transient MCA occlusion. The effect of ischemia on cortical activity and axonal conduction was differentially studied by proximal or distal occlusion of the MCA. Regional cerebral blood flow changes in the forelimb area were monitored by laser-Doppler flowmetry during ischemia and reperfusion. In addition, synaptic transmission within the forelimb area of motor cortex was examined by intracellular and extracellular recording of potentials generated by stimulation of the premotor area. No MEP response was recorded during ischemia. Upon reperfusion: (i) motor axons readily regained their excitability and cortical stimulation caused successive pyramidal volleys (recorded as D waves from the brain stem) and a MEP from contralateral paralytic muscles although synaptic activation of motor pathways was not feasible; (ii) the amplitude of pyramidal volley was increased; (iii) MEPs with a longer latency were recorded from the ipsilateral forelimb. In conclusion, differential recovery of synapses and axons after ischemia may account for some previously unexplained findings (such as preserved MEPs in paralysed muscles) observed in cortical stimulation studies of stroke patients.     

Synthesis and anticonvulsant activity of some new 4-aryl-4-imidazoline-2-one derivatives.

In this study, some new 4-aryl-4-imidazoline-2-one derivatives have been prepared by the reaction of potassium cyanate with some aminoethanone hydrochlorides. The structure of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (ScMet) tests according to the ADD (Antiepileptic Drug Development) programme Phase I. Neurotoxicity of the compounds was evaluated by rotarod test. While 2 of the compounds showed protection against ScMet induced seizures at 30 and 300 mg/kg dose levels, 3 of the compounds showed neurotoxicity.     

In vitro/in vivo studies on a buccal bioadhesive tablet formulation of carbamazepine

A buccoadhesive controlled-release system for delivery of carbamazepine (CBZ) was prepared by compression of hydroxypropyl methylcellulose (HPMC) and carbomer, incorporating a penetration enhancer, sodium glycodeoxycholate (GDC). The release behaviour of systems containing CBZ and various amounts of the two polymers with and without GDC was found to be non-Fickian. Formation of an interpolymer complex between HPMC and carbomer was confirmed in acidic medium by turbidity, viscosity and FT-IR measurements. Addition of the drug to the buccoadhesive formulation reduced the adhesion force significantly (p < 0.1). GDC did not have any effect on bioadhesion. Permeability of bovine buccal mucosa to CBZ was determined using Ussing diffusion chambers [1]. In vivo interaction between the tablet and tissue was examined histologically as well as by scoring mucosal irritation. Histological changes observed in the buccal epithelium after 4 h contact with the tablets containing GDC recovered completely within 24 h after removal. No measurable plasma level of CBZ was obtained either in the absence or presence of GDC.     

Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis?

Substantial experimental data and recent clinical evidence suggesting that tissue reperfusion is a better predictor of outcome after thrombolysis than recanalization necessitate that patency of microcirculation after recanalization should be reevaluated. If indeed microcirculatory blood flow cannot be sufficiently reinstituted despite complete recanalization as commonly observed in coronary circulation, it may be one of the factors contributing to low efficacy of thrombolysis in stroke. Although microvascular no-reflow is considered an irreversible process that prevents tissue recovery from injury, emerging evidence suggests that it might be reversed with pharmacological agents administered early during recanalization. Therefore, therapeutic approaches aiming at reducing microvascular obstructions may improve success rate of recanalization therapies. Importantly, promoting oxygen delivery to the tissue, where entrapped erythrocytes cannot circulate in capillaries, with ongoing serum flow may improve survival of the underreperfused tissue. Altogether, these developments bring about the exciting possibility that benefit of reperfusion therapies can be further improved by restoring microcirculatory function because survival in the penumbra critically depends on adequate blood supply. Here, we review the available evidence suggesting presence of an ‘incomplete microcirculatory reperfusion'' (IMR) after focal cerebral ischemia and discuss potential means that may help investigate IMR in stroke patients after recanalization therapies despite technical limitations.     

Nipecotic acid, an uptake blocker, prevents fading of the gamma-aminobutyric acid effect

In rats under urethane, iontophoretic applications of GABA (30-60 nA) in the str. pyramidale of CA1, showed a rapidly fading inhibitory effect. By contrast, GABA had a well-maintained inhibitory effect in str. radiatum. During iontophoresis of nipecotic acid (30-85 nA) identical applications of GABA in str. pyramidale caused a more prominent depression without fading, which suggests that removal of GABA, by uptake, can at least in part account for 'fading'. Nipecotic acid also prolonged the paired-pulse inhibition, presumably by prolonging the duration of inhibitory postsynaptic potentials.