Neurodegeneration in familial amyloidotic polyneuropathy

Familial amyloid polyneuropathies (FAP) constitute a group of inherited amyloidoses that affect peripheral nerves. One common form of FAP is caused by transthyretin (TTR) misfolding and deposition in the peripheral nervous system, leading to neuronal toxicity and death. The molecular mechanisms responsible for this toxicity are unclear; however, there is good biochemical and histopathological evidence that the toxicity of TTR mutations is correlated to their aggregation state. In addition, neuronal calcium dysregulation is a mechanism that has been suggested to drive the pathogenesis of FAP. Amyloidogenic TTR mutations cause significant calcium influx via L-type calcium channels in neuronal cell lines, while in primary sensory neurons, TTR mediates a calcium influx via a novel mechanism of transient receptor potential melanostatin (TRPM8) and voltage-gated sodium and calcium channel activation. Significantly, calcium dysregulation is a pathological hallmark of other neurodegenerative diseases involving amyloidosis, for example Alzheimer's disease, and this mechanism could explain the molecular events that drive amyloid toxicity in other neurodegenerative diseases.     

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.

Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.

Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.     

Effect of infused L-threo-3,4-dihydroxyphenylserine on adrenergic activity in patients with familial amyloid polyneuropathy

Summary L-threo-3,4-dihydroxyphenylserine (DOPS), an immediate precursor amino acid of (-)-norepinephrine, was used as a pharmacological tool to investigate the pathophysiology of the peripheral sympathetic nervous system in Type 1 familial amyloid polyneuropathy. Patients with the well-established disorder showed an enhanced pressor reponse to L-threo-DOPS under conditions that produced no change in normal subjects. While octopamine induced a brisk pressor response, L-threo-DOPS produced a slow and prolonged change in blood pressure, with a marked concomitant increase in urinary excretion of norepinephrine. A slight increase in urinary excretion of total metanephrine was observed in both groups, but there was no significant increase in serum dopamine--hydroxylase activity. Since infusion of dilute norepinephrine into patients also produced a markedly hypersensitive response, the characteristic pressor response to L-threo-DOPS was indicative of denervation supersensitivity of adrenergic receptors to norepinephrine formed enzymatically from L-threo-DOPS.     

Pharmacokinetic studies of oral L-threo-3,4-dihydroxyphenylserine in normal subjects and patients with familial amyloid polyneuropathy

Summary The pharmacokinetics of oralL-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, andL-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column.L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism ofL-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oralL-threo-DOPS were essentially equal to those of twice as large a dose ofDl-threo-DOPS.An outline of this study was presented at the Eighth International Congress of Pharmacology, Tokyo, 19–24th July, 1981     

Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD₅₀. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (>90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.Part of this work was presented at the 25th Annual Meeting of the Society of Toxicology held in New Orleans, LA, USA, March 1986, at the International Symposium on Biochemical and Cellular Indices of Toxicity in Occupational and Environmental Medicine held in Milan, Italy, June 1986, and at the 9th Meeting of the Peripheral Nerve Study Group, Praglia (PD), Italy, August – September, 1989     

Organophosphate-induced delayed polyneuropathy

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.     

Blood copper in organophosphate-induced delayed polyneuropathy

Some organophosphorous esters cause a polyneuropathy which becomes clinically evident 2 weeks after a single dose. The pathogenesis involves modifications of a target protein, neuropathy target esterase, in the axons and a selective inhibition of retrograde axonal transport. It was suggested that copper metabolism might also be involved because of increased levels of plasma copper and ceruloplasmin in animals developing this polyneuropathy. Our results do not confirm this observation; treatment of hens with highly neuropathic single doses of two organophosphates (dihexyl-2,2-dichlorovinyl phosphate and mono-o-cresyl diphenyl phosphate) does not affect total and plasma free copper when measured several times during the development of polyneuropathy. We concluded that copper homeostasis is not affected and that copper changes are unlikely to be involved in the pathogenesis of this polyneuropathy.     

Organophosphate induced delayed polyneuropathy

This review discusses the current understanding of organophosphate induced delayed polyneuropathy (OPIDP) with emphasis on molecular mechanisms, pathogenesis and possibilities for prevention/therapy. OPIDP is a rare toxicity caused by certain organophosphorus compounds (OP) characterized by degeneration of some long axons in the central and peripheral nervous system that appear about 2-3 weeks after exposure. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). NTE can be inhibited by two types of inhibitors: a) phosphates, phosphonates, and phosphoramidates, which cause OPIDP when >70% of the enzyme is inhibited, and b) phosphinates, carbamates, and sulfonyl halides which inhibit NTE and cause either protection from, or promotion, of OPIDP when given before or after a neuropathic OP, respectively. The ability of a NTE inhibitor to cause OPIDP, besides its affinity for the enzyme, is related to its chemical structure and the residue left attached to the NTE. If such residues undergo the aging reaction i.e. the loss of an alkyl group bound to the enzyme, those OPs usually have a high likelihood of causing OPIDP. Protection from neuropathic doses of OP inhibitors is obtained when NTE is inhibited with nonageable inhibitors. Promotion of OPIDP involves another site besides NTE because it can occur when all NTE is affected. It is now known that this other site is similar to NTE in that it is also sensitive to mipafox but at much higher concentrations. Promotion affects either the progression or expression of OPIDP after the initial biochemical effect on NTE. Some recent observations suggest that development of OPIDP in hens can be influenced by atropine, oximes and methylprednisolone when they are given before or soon after neuropathic OPs.     

转甲状腺素蛋白的化学修饰物在肺感染性疾病诊断中的作用

目的:探讨转甲状腺素(TTR)蛋白含量和化学修饰类型在诊断肺感染性疾病中的作用。方法:(1)测定22例肺感染患者血清和胸腔积液中总蛋白(TP)、白蛋白(ALB)、三酰甘油(TG)、胆固醇(Cho)、载脂蛋白(Apo)A、ApoB、乳酸脱氢酶(LDH)、腺苷脱氨酶(ADA)、葡萄糖(GLU)和TTR等指标水平。(2)基质辅助激光电离飞行时间质谱(MALDI-TOF-MS)分析肺感染患者血清和胸腔积液TTR蛋白的化学修饰;作为对照测定16例健康人血清TTR的修饰。结果:(1)胸腔积液TG、Cho、TTR、ApoA、ApoB、TP、ALB和GLU指标水平均明显低于血清,仅ADA指标增高,差异有统计学意义(P<0.05或P<0.01)。(2)蛋白指标中TTR减低最明显。(3)肺感染患者胸腔积液和血清中只发现两种修饰类型,而无对照组的cysgly-TTR修饰型。结论:血清及胸腔积液中TTR含量和cysgly-TTR的减少,可能作为辅助诊断肺感染指标。     

The pathogenesis of organophosphate polyneuropathy.

This review discusses the facts regarding organophosphate-induced delayed polyneuropathy (OPIDP) as they are related to its pathogenesis rather than being a comprehensive review of all available data. Neuropathy target esterase (NTE) is considered to be the molecular target for OPIDP which is affected by several esterase inhibitors. Such inhibitors are ranked according to their toxicological effects as follows: 1. Phosphates, phosphoroamidates, and phosphonates cause OPIDP when high amounts of NTE are inhibited. In most cases 70 to 80% inhibition is enough, whereas in others much more is required. 2. Phosphinates, carbamates, and sulfonyl halides cause either protection from or promotion of OPIDP when given before or after a neuropathic OP, respectively. Both effects are related to doses that inhibit NTE. Neuropathy is also caused by the combined treatment with a carbamate and a sulfonyl fluoride. The potency of a given NTE inhibitor to cause OPIDP is related to the chemistry of the residue left attached to NTE, in addition to its affinity for the enzyme. The capability of inhibited NTE to undergo the aging process distinguishes inhibitors with high from those with negligible or very low potency to cause OPIDP. Therefore, protection from neuropathic doses of effective OPs is obtained when NTE is mostly inhibited with nonageable inhibitors. Promotion of OPIDP is likely to involve another site besides NTE because it might occur when almost all NTE is affected. Promotion affects either progression or expression of OPIDP after the initial biochemical lesion on NTE. Since only NTE inhibitors have been proven to be promoters, it is possible that this site is made available after the initiation of OPIDP and that it may have biochemical properties indistinguishable from those of NTE of na?ve birds. Age-related resistance to OPIDP also seems to be related to either progression or expression of OPIDP and/or to the different physiology of NTE at a given age. Previously reported resistance of rats to clinical OPIDP seems also to be age-dependent. The physiological function(s) of NTE is unknown, but some practical gains have been obtained from its identification, including OPIDP risk assessment and biomonitoring.     

Biological monitoring for organophosphate-induced delayed polyneuropathy

Certain organophosphate (OP) pesticides cause a delayed polyneuropathy. The two-step initiation mechanism for this toxicity involves the phosphorylation and subsequent 'aging' of a protein in the nervous system called Neuropathy Target Esterase (NTE). The observation of this enzyme activity in peripheral blood lymphocytes led to several studies to verify whether its measurement after OP exposures might be used as a biological monitoring test for the OP-induced delayed polyneuropathy (OPIDP). The evidence, so far, on the use of this biochemical test in man is discussed together with the need for further research.     

Effects of Modification of Transthyretin on Diagnosis of Infectious Lung Disease

目的:探讨转甲状腺素(TTR)蛋白含量和化学修饰类型在诊断肺感染性疾病中的作用.方法:(1)测定22例肺感染患者血清和胸腔积液中总蛋白(TP)、白蛋白(ALB)、三酰甘油(TG)、胆周醇(Cho)、载脂蛋白(Apo)A、Apo B、乳酸脱氢酶(LDH)、腺苷脱氨酶(ADA)、葡萄糖(GLU)和TTR等指标水平.(2)基质辅助激光电离飞行时间质谱(MAL-DI-TOF-MS)分析肺感染患者血清和胸腔积液TTR蛋白的化学修饰;作为对照测定16例健康人血清TTR的修饰.结果:(1)胸腔积液TG、Cho、TTR、ApoA、ApoB、TP、ALB和GLU指标水平均明显低于血清,仅ADA指标增高,差异有统计学意义(P＜0.05或P＜0.01).(2)蛋白指标中TTR减低最明显.(3)肺感染患者胸腔积液和血清中只发现两种修饰类型,而无对照组的cysgly-TTR修饰型.结论:血清及胸腔积液中TTR含量和cysgly-TTR的减少,可能作为辅助诊断肺感染指标.     

Clinical outcomes of critical illness polyneuropathy

It is often difficult to isolate the origin of acute weakness in the critically ill population because of multiple etiologies. Aminoglycosides, corticosteroids, and neuromuscular blockers frequently are implicated as the source of acute weakness. Recently, critical illness polyneuropathy (CIP), a syndrome of unknown etiology, was added to the differential diagnosis. The frequency of CIP is approximately 70% in patients with sepsis. Early studies of CIP, which were mostly retrospective, underestimated its frequency due to the complexity of the diagnosis and unfamiliarity with the syndrome. Prospective studies have explored the causality and clinical outcomes of CIP Clinical outcomes of patients with CIP include difficulty weaning from mechanical ventilation, increased length of stay, prolonged recovery, and an overall mortality rate of 26-71%. The association of CIP with sepsis, multiorgan failure, and drugs is still unclear.     

Synthesis and Evaluation of Monoaryl Derivatives as Transthyretin Fibril Formation Inhibitors

Pharmaceutical Chemistry Journal - Transthyretin (TTR) is a homo-tetrameric protein characterized by four identical β-sheet rich monomers assembled together to form a tetramer that is crossed,...     

Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data

Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia. Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions. In the past several years, experimental drugs--such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors--have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis. Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits.     

Clinical expression of organophosphate-induced delayed polyneuropathy in rats.

Single doses of certain organophosphates (OP), such as dibutyl-2,2-dichlorovinyl phosphate (DBDCVP) cause organophosphate-induced delayed polyneuropathy (OPIDP) in hens. Clinical effects correlate with inhibition of neuropathy target esterase (NTE) which is considered the target for this toxicity. Pre-treatment with non-neuropathic NTE inhibitors, such as phenylmethanesulfonyl fluoride (PMSF), protects from OPIDP. However, when given after OPs, these compounds promote OPIDP. Chicks are relatively resistant to OPIDP despite high NTE inhibition. It has also always been reported that rats represent a species which is resistant to OPIDP and that they might develop morphological but not clinical signs of OPIDP. We report here that clinical OPIDP can be produced in 3.5- and 6-month-old rats by DBDCVP (5 mg/kg s.c.) and that it correlates with high (> 90%) NTE inhibition. When PMSF (120 mg/kg s.c. x 2) was given after DBDCVP, OPIDP was promoted. Pretreatment with PMSF protected from OPIDP. We conclude that resistance to OPIDP in the rat is age-related, as it is in the hen.