Polyamines with N-(3-phenylpropyl) substituents are effective competitive inhibitors of trypanothione reductase and trypanocidal agents.

Several N-(3-phenylpropyl)-substituted spermidine and spermine derivatives were prepared and found to be potent competitive inhibitors of Trypanosoma cruzi trypanothione reductase (seven compounds with Ki values < 5 microM are described). The most effective inhibitor studied was compound 12 with a Ki value of 0.151 microM. Six of the compounds described are also effective trypanocides with IC50 values < 1 microM.

Abnormal development of biceps brachii phasic stretch reflex and persistence of short latency heteronymous reflexes from biceps to triceps brachii in spastic cerebral palsy.

Co-contraction of antagonist muscles is characteristic of spasticity arising from perinatal brain damage but not in spasticity occurring after brain damage in adulthood. Such co-contraction is a normal feature of early post-natal motor development. Heteronymous, monosynaptic Group Ia projections from biceps brachii to both the antagonist triceps brachii and to other synergist and non-synergist muscles of the upper limb occur in the newborn baby and become restricted during the first 4 years to motor neurons of primarily synergistic muscles. Longitudinal and cross-sectional studies have been performed to test the hypothesis that inappropriate heteronymous excitatory projections persist in children with perinatal brain damage who develop spasticity. Subjects with spasticity, from brain damage acquired in adulthood were also studied to determine if these projections simply become unmasked as part of spasticity, independent of the age of occurrence of the brain damage. Twenty-nine healthy newborn babies and 29 at high risk for cerebral palsy, 12 of whom developed spastic quadriparesis, were studied longitudinally for 4 years. Thirty-eight subjects, aged 8-30 years, with spasticity of perinatal origin (11 hemiplegic, 11 quadriplegic, 16 with Rett syndrome) and 11 subjects with stroke in adulthood and spastic hemiplegia were also studied. The results were compared with those obtained in 372 normal subjects aged from birth to 55 years. Small taps were delivered to the tendon of biceps brachii using an electromechanical tapper. Surface EMG was recorded from biceps and triceps brachii, pectoralis major and deltoid. In the longitudinal study, those developing spastic quadriparesis showed persistent low thresholds for the homonymous phasic stretch reflex, which had abnormally short onset latencies. There was persistence of short onset heteronymous excitatory responses in triceps brachii, while a normal pattern of restriction of heteronymous responses to pectoralis major and deltoid occurred. The same pattern was observed in older subject groups with spasticity of perinatal origin. In adults with hemiplegia following stroke the threshold of the homonymous phasic stretch reflex was low, but it had a normal onset latency. There was no evidence of abnormal heteronymous excitatory responses. In conclusion, exaggerated excitatory responses to primary muscle afferent input were observed in the homonymous (biceps brachii) and antagonist (triceps brachii) motor neurons in subjects with spasticity arising from perinatal brain damage. They are likely to play an important role in the predominant co-contraction of agonist/antagonist muscles during voluntary movement observed in subjects with spastic cerebral palsy.

Polyamine derivatives as inhibitors of trypanothione reductase and assessment of their trypanocidal activities.

Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the antioxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4,N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with Ki values of 3.5, 5.5 and 9.5 microM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 microM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique pathway in Trypanosomatidae have potential as antitrypanosomal agents.

Inhibiting effects of spermidine derivatives on Trypanosoma cruzi trypanothione reductase.

Trypanothione reductase is a vital component of the antioxidant defenses of trypanosomes. This enzyme reduces trypanothione, a spermidine-glutathione conjugate. The inhibitory effects of several spermidine derivatives on the reduction of trypanothione by Trypanosoma cruzi trypanothione reductase were assessed. Spermidine derivatives containing hydrophobic aromatic substituents were found to be competitive inhibitors of trypanothione reductase. N4-acylated spermidine derivatives were less effective inhibitors than the corresponding N4-alkylated derivatives. The most effective compounds studied were N1, N8-bis(2-naphthylmethyl)spermidine and N4-(2-naphthylmethyl)spermidine, with Ki values of 9.5 and 108 microM, respectively.

Radiation of phasic stretch reflex in biceps brachii to muscles of the arm in man and its restriction during development.

1. The phasic stretch reflex in biceps brachii has been recorded in 372 normal subjects aged from 31 weeks gestation to 55 years. The stimulus used was a brief mechanical pulse delivered by a hand-held electromagnetic vibrator and the response was measured in the surface electromyogram. 2. The threshold for eliciting the reflex was low in the newborn and increased over the first 6 years to values corresponding to those of adults. 3. On the basis of timing it is concluded that the phasic stretch reflex has a monosynaptic component at all ages. 4. The surface electromyogram was also recorded in triceps brachii, pectoralis major, deltoid and hypothenar muscles. In some subjects evoking the phasic stretch reflex in biceps brachii resulted in short latency responses in these muscles, a phenomenon termed radiated response. 5. The probability of occurrence of radiated responses and their magnitudes were greatest at birth and decreased over 2-4 years. 6. Experiments were performed to determine how far mechanical transmission of the stimulus to biceps through the tissues of the arm might account for the radiated responses in the other muscles studied. It was concluded that the responses observed in triceps brachii, pectoralis major, deltoid and hypothenar muscles, following vibration of the biceps tendon, are primarily due to the radiation of the activity carried in biceps muscle afferents to the alpha-motoneurones of the respective muscles. 7. On the basis of timing it is concluded that in subjects below 2 years the radiated responses in the muscles studied have a monosynaptic component.

Molecular features necessary for the uptake of diamines and related compounds by the polyamine receptor of rat lung slices.

The influence of 17 putrescine analogues on the uptake of putrescine and/or paraquat by rat lung slices has been determined. Most of these compounds are competitive inhibitors of putrescine and/or paraquat uptake, but three show no inhibiting activity. Apparent Ki values of the putrescine derivatives increase, and thus the inhibitory effects decrease, with increasing N-methylation. Comparison of N-methyl-1,4-diaminobutane (Ki = 8 microM) with N,N'-bis-methyl-1,4-diaminobutane (Ki = 25.5 microM) shows that a single primary amino group is desirable for high inhibiting activity. Dimethylation at one amino function does not greatly decrease inhibitory potential (thus N,N-dimethyl-1,4-diaminobutane has Ki = 11.5 microM). Increasing the size of N-alkyl substituents in putrescine derivatives, decreased their inhibitory action on the uptake of putrescine. Investigation of the effect of conformationally-restricted analogues of putrescine shows that both (E) and (Z) isomers of 1,4-diaminobut-2-ene are poor inhibitors of putrescine uptake. Analogues of putrescine with bulky substituents on the butyl chain, i.e. the meso- and rac-isomers of 1,1-dichloro-2,3-diaminomethylcyclopropane, do not inhibit putrescine uptake. Inhibiting putrescine derivatives which contain aziridine groups are competitive inhibitors of putrescine and paraquat uptake. Surprisingly, N-(4-aminobutyl)aziridine is the most effective inhibitor of putrescine uptake studied, and is a better inhibitor of paraquat uptake than the endogenous polyamine, putrescine. N-(4-Aminobutyl)aziridine binds reversibly to the polyamine transporter and its inhibitory effects do not appear to be due to any cytotoxic activity of the aziridine. The parameter A (mM)-1 defined as 1000/Ki (where Ki units are microM) was taken as a measure of the affinity of a compound for the polyamine receptor in this paper.

Neurophysiological observations on corticospinal projections to the upper limb in subjects with Rett syndrome.

The aim of the present study was to investigate the excitability of corticospinal neurons and the integrity of their projections to the alpha motor neurons through the corticospinal tract in subjects of different ages with Rett syndrome. Electromagnetic stimulation of the motor cortex and cervical motor roots was used to evoke motor action potentials in the biceps brachii and hypothenar muscles. The phasic stretch reflex in the biceps brachii was also recorded to study the excitability of spinal alpha motor neurons. Motor cortex stimulation evoked motor action potentials at low threshold and with abnormally short latencies and prolonged durations. In contrast cervical motor root stimulation resulted in responses of normal latency and duration. The phasic stretch reflex had a low threshold, short latency and prolonged duration. It is concluded that in Rett syndrome the corticospinal pathway is intact. The results suggest disordered synaptic control of the Betz cell of the motor cortex and/or the spinal alpha motor neuron, although the involvement of the latter might be a consequence of dysfunction in supraspinal descending motor pathways.