Abstract Acidic fibroblast growth factor (aFGF) is a potent neurotrophic factor that may uphold neuronal survival in the injured spinal cord. It has been reported to promote functional recovery in open-label clinical studies. The first randomized, double-blind, placebo-controlled study was conducted to verify aFGF’s efficacy and safety in SCI patients. Patients with AIS Grade A or B SCI were randomized into two arms and given either aFGF or placebo every 4 weeks for total 3 doses. All patients were evaluated for medical, neurological, and functional changes at baseline, then every 4 weeks after the first dose of aFGF/placebo until 48 weeks. The first dose was administered directly to the injured site at the surgery within 6 weeks after SCI, and the 2nd and 3rd doses were given through lumbar puncture. Due to the impact of COVID-19 pandemic the study ended prematurely; nevertheless, explorative analyses revealed encouraging signals of the beneficial effect of aFGF albeit with a limited sample size. This is the first clinical report showing that aFGF may reduce myelomalacia and accelerate motor recovery in complete SCI patients with a significantly higher chance to achieve a 10-point improvement (Odds ratio = 6.06). Further studies to validate aFGF’s clinical efficacy are warranted.
The work described in this thesis attempts to answer experimentally some questions that have arisen in the clinical treatment of Parkinson's Disease. Namely 1) Dose the time course of plasma dopa and its metabolites after systemic administration alone and after benserazide (a peripheral dopa decarboxylase inhibitor) reflect those found in the striatum and the effect on striatal neurones? 2) What is the effect of OMD, the O-methylated metabolite of dopa, on the uptake of L-dopa into the brain and the synthesis and release of dopamine? Automated high performance liquid chromatography with electrochemical detection was employed to determine the levels of dopa, dopamine and their metabolites DOPAC, HVA and OMD in plasma samples and in striatal and hippocampal perfusates (obtained by microdialysis) in halothane anaesthetized rats as well as in slices perfusates and brain tissue. Striatal neurone firing was monitored with extracellular single unit recording in intact and 6-hydroxydopamine lesioned rats. Dialysis showed that the time course of increased striatal and hippocampal L-dopa, dopamine and metabolites correlated significantly with those in plasma after 15mgKg intravenous L-dopa or 15, 50 and 100 mgKg-1 L-dopa methyl ester. After L-dopa with benserazide, plasma and CSF dopa levels were significantly higher and longer lasting although dopamine was absent from plasma and significantly lower in CSF similar CSF levels of DOPAC and HVA were obtained despite very low levels in plasma. This suggests that dopamine is formed from L-dopa crossing the blood brain barrier but it seems likely that the origin of dopamine synthesized from dopa in the presence of benserazide is different from that after L-dopa alone. This was also supported by difference in the responses of striatal neurons to L-dopa in the absence and presence of benserazide. Inhibition of such neurons did not correlate directly with CSF dopa, dopamine, DOPAC and HVA and was surprisingly less marked after benserazide. Acute lesions of the nigra striatal tract with 6-hydroxydopamine reduced the inhibitory effect of L-dopa on neuron firing and although this was restored as supersensitivity developed over two weeks. Subchronic treatment with L-dopa partially reversed it in a manner consistent with dopamine not being synthesized in dopaminergic terminal. Intravenous dopamine also inhibited striatal neurone firing and from its appearance in plasma and dialysates after L-dopa it is possible that it can cross the BBB. No evidence was obtained that high plasma OMD affected dopa entry into the brain. Superfusion of striatal slices with L-dopa (10μM) elevated tissue content of dopamine as well as increasing its spontaneous and K+- induced efflux. OMD significantly reduced both effluxes whilst significantly increasing the tissue levels of dopa and DA suggesting it reduces release of dopamine formed from exogenous L-dopa. The results are discussed in respect of the mode of action and loss of efficacy of L-dopa in Parkinsonian patients and the role of OMD.
The effects of L ‐dopa methylester (LDME), an analogue of levodopa, on the spontaneous activity of dopamine sensitive neurones in the rat striatum, after 6‐hydroxydopamine induced degeneration of the nigrostriatal tract were compared with those in unlesioned animals both in the absence and presence of benserazide, a peripheral DOPA decarboxylase inhibitor (PDI). Studies were performed at 5–7 days post lesion (group 1 animals), at 21 days (group 2) when denervation supersensitivity was evident by contralateral turning to apomorphine and at the same time but following 7 days dosing with LDME plus benserazide (group 3). In unlesioned animals, LDME alone inhibited spontaneous firing by some 45% over 60 min including a marked but transient early phase which was still present in all lesioned animals even though the later inhibition was significantly reduced in group 1 and 3 animals. When given after benserazide in unlesioned animals LDME still produced a similar level of overall inhibition but without the early phase. The lesion reduced the overall inhibition, except in group 2 animals, and after chronic dosing (group 3) it was almost absent. It is proposed that since the early inhibition with LDME alone is still seen after lesion of the nigrostriatal tract but not after the PDI benserazide, it is caused by peripherally formed dopamine and that as the delayed inhibition with LDME alone and after benserazide are all reduced by nigrostriatal lesions, as is its amphetamine like ipsilateral turning, that this depends on locally (striatal) synthesized dopamine. This study also shows that chronic levodopa/PDI treatment reduces the compensating increased activity of surviving dopaminergic neurones and the functional supersensitivity to dopamine suggests that the long term administration of levodopa may reduce its own utilization and activity in the striatum and in the treatment of Parkinson's Disease. British Journal of Pharmacology (1997) 121 , 331–337; doi: 10.1038/sj.bjp.0701133
This study aims to evaluate the potential benefits of treating spinal cord injury (SCI) patients with acidic fibroblast growth factor (aFGF), a potent neurotrophic factor that preserves neuronal survival. The study involved 12 tetraplegic patients with American Spinal Injury Association Impairment Scale (AIS) Grade A SCI who were randomly assigned to receive either a recombinant human aFGF or a placebo every 4 weeks for three doses. Participants underwent comprehensive evaluations of medical, neurological, and functional parameters at baseline and every 4 weeks after the first dose until the 48th week. The first dose was administered directly to the injury site during surgery within 6 weeks of the SCI, while the subsequent two doses were administered via lumbar puncture with a 4-week interval. The results revealed promising beneficial effects of aFGF on AIS Grade A SCI patients. The study report highlights aFGF's potential to expedite motor recovery in complete SCI patients and significantly increase the probability of a 10-point improvement when compared to the placebo group (odds ratio = 6.06,
1 . The effect of L-dopa on the spontaneous and KCl-evoked efflux of dopamine from rat striatal slices, measured by high performance liquid chromatography (h.p.l.c.) with electrochemical detection (e.c.d.) was investigated in the absence and presence of 3-O-methyl dopa (OMD), an O-methylated metabolite of L-dopa. 2 . The addition of exogenous L-dopa (10 μm) significantly increased both the spontaneous efflux of dopamine and that evoked by KC1. 3 . In the presence of 50 μm OMD, the effects of L-dopa on the spontaneous and KCl-evoked efflux of dopamine were smaller but only the former was significantly different from that in the absence of OMD. However, the total efflux of dopamine during the overall superfusion time (70 min) including KC1 depolarization was significantly lower than in the absence of OMD. 4 . Analysis of tissue content after superfusion revealed that the levels of dopa and dopamine in slices superfused with L-dopa in the presence of OMD were significantly higher than those superfused with L-dopa alone. 5 . The finding that OMD significantly reduced the efflux of dopamine whilst increasing its concentration in striatal slices after L-dopa superfusion could explain the reduced efficacy seen after long-term therapy with L-dopa and a peripheral dopa decarboxylase inhibitor in Parkinsonian patients when plasma and brain OMD are very high.
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