Role of chondroitin sulfate proteoglycans (CSPGs) in synaptic plasticity and neurotransmission in mammalian spinal cord.

Chronic unilateral hemisection (HX) of the adult rat spinal cord diminishes conduction through intact fibers in the ventrolateral funiculus (VLF) contralateral to HX. Intraspinal injections of Chondroitinase-ABC, known to digest chondroitin sulfate proteoglycans (CSPGs) in the vicinity of injury, prevented this decline of axonal conduction. This was associated with improved locomotor function. We further injected three purified CSPGs into the lateral column of the uninjured cord at T10: NG2 and neurocan, which increase in the vicinity of a spinal injury, and aggrecan, which decreases. Intraspinal injection of NG2 acutely depressed axonal conduction through the injection region in a dose dependent manner. Similar injections of saline, aggrecan, or neurocan had no significant effect. These results identify a novel acute action of CSPGs on axonal conduction in spinal cord, and suggest that antagonism of proteoglycans reverses or prevents the decline of axonal conduction, in addition to stimulating axonal growth

Chronic thoracic hemisection spinal cord injury in adult rats induces a progressive decline in transmission from uninjured fibers to lumbar motoneurons

Although most spinal cord injuries are anatomically incomplete, only limited functional recovery has been observed in people and rats with partial lesions. To address why surviving fibers cannot mediate more complete recovery, we evaluated the physiological and anatomical status of spared fibers after unilateral hemisection (HX) of thoracic spinal cord in adult rats. We made intracellular and extracellular recordings at L5 (below HX) in response to electrical stimulation of contralateral white matter above (T6) and below (L1) HX. Responses from T6 displayed reduced amplitude, increased latency and elevated stimulus threshold in the fibers across from HX, beginning 1-2 weeks after HX. Ultrastructural analysis revealed demyelination of intact axons contralateral to the HX, with a time course similar to the conduction changes. Behavioral studies indicated partial recovery which arrested when conduction deficits began. These findings suggest a chronic pathological state in intact fibers and necessity for prompt treatment to minimize it

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Distributions of EPSP Latency at Different Group Ia-Fiber-Alpha-Motoneuron Connections

1. Distributions of synaptic latency of single spike-triggered excitatory postsynaptic potentials (EPSPs) have been compared at different group Ia-fiber-alpha-motoneuron connections in the cat. 2. These distributions differ in standard deviation. When the latencies at different connections are measured from the terminal potential, which may signal the arrival of the Ia-fiber impulse in the terminals, the mean is also found to vary from connection to connection. 3. The mean and standard deviation exhibit a significant positive linear correlation. It can be shown that the minimum latency for all these distributions is about the same. 4. The amplitude of averaged EPSPs at these connections was found to be closely related to parameters of the latency distribution. 5. Latency of the averaged EPSP was found to be intermediate between the minimum and mean latency observed in single trials. 6. These variations in distribution of latencies may result from the action of different numbers of release sites (e.g., boutons) at different connections. However, differences in characteristics of transmitter release at different connections have not been ruled out

Parallel Fluctuations of EPSP Amplitude and Rise Time with Latency at Single Ia-Fiber-Motoneuron Connections in the Cat

1. Membrane potential was recorded intracellularly from motoneurons in the lumbosacral spinal cord in cats. Single sweeps triggered by impulses in a single Ia-fiber projecting to the impaled motoneuron were digitized at 20-µs resolution and stored on magnetic tape. 2. Analysis of many of these records confirmed that the latency of excitatory postsynaptic potentials (EPSPs) produced by activity in single Ia-fibers fluctuates from trial to trial. Distributions of EPSP latency differed at each Ia-motoneuron combination with regard to their variance, although all were unimodal. 3. A uniform finding was that the EPSPs evoked with short latencies from the Ia trigger pulse are larger in peak amplitude than those with longer latency. EPSP amplitudes decrease monotonically as latency increases throughout the range of latencies. 4. EPSP rise time also decreases steadily as latency increases. EPSP half-width tends to decrease with latency, but not as consistently as rise time. 5. Voltage fluctuations unrelated to the trigger, i.e., noise, did contribute to our measurements of variability in EPSP parameters. However, analyses designed to estimate this contribution suggest that the spike-triggered EPSPs vary significantly beyond what can be ascribed to noise. 6. None of the fluctuations in amplitude, latency, and rise time was correlated with the instantaneous rate of discharge of the Ia-fiber (3-40 pulses/s). 7. These fluctuations could not be related to variability in postsynaptic parameters, e.g., membrane potential, time constant, or locus of synaptic activation. 8. These data are most consistent with the view that the origin of fluctuations in these EPSP parameters is presynaptic. Our evidence supports the conclusion that fluctuations result from the stochastic nature of transmitter release rather than from variability in axonal conduction or bouton invasion

Fluctuations in Group Ia EPSPs: Consequences for Mechanisms of Transmitter Release and Measured Parameters of Averaged EPSPs

This is a chapter in Regulatory Functions of the CNS: Principles of Motion and Organization, which contains the proceedings of the 28th International Congress of Physiological Sciences

Fluctuations in Group Ia EPSPs: Consequences for Mechanisms of Transmitter Release and Measured Parameters of Averaged EPSPs

This is a chapter in Regulatory Functions of the CNS: Principles of Motion and Organization, which contains the proceedings of the 28th International Congress of Physiological Sciences

Nerve growth factor-induced hyperalgesia in the neonatal and adult rat

Recently, we have shown that the interaction between NGF and sensory neurons in early postnatal periods is restricted to nociceptive afferents (Ritter et al., 1991; Lewin et al., 1992a; Ritter and Mendell, 1992). Here we show that administration of excess NGF to neonatal or mature animals can lead to a profound behavioral hyperalgesia. Neonatal NGF treatment (postnatal day O-14) resulted in a profound mechanical hyperalgesia that persisted until the animals had reached maturity (6 weeks of age). This hyperalgesia could be explained by an NGF-mediated sensitization of A6 nociceptive afferents to mechanical stimuli. This peripheral sensitization wore off with a time course similar to that of the behavioral hyperalgesia. Treatment of animals from the second postnatal week until 5 weeks of age (juveniles) led to a very similar behavioral hyperalgesia; however, there was no corresponding sensitization of A6 nociceptors to mechanical stimuli. Finally, one group of adult animals (5 weeks old) was treated daily with single injections of NGF for between 1 and 4 d. Within 24 hr after the first NGF injection these animals developed a mechanical hyperalgesia of the same magnitude seen after neonatal and juvenile NGF treatments. No sensitization of A6 nociceptive afferents was observed in these animals. In addition to the mechanical hyperalgesia, the animals also developed a heat hyperalgesia after one injection of NGF. The heat hyperalgesia was apparent within 15 min after the injection; however, signs of mechanical hyperalgesia were not seen until 6 hr after the injection. In conclusion, it appears that the NGF-induced mechanical hyperalgesia is brought about by different mechanisms in neonatal and adult rats. Furthermore, in adult animals the NGFinduced mechanical and heat hyperalgesia also appear to be attributable to two different mechanisms. The mechanical hyperalgesia may be due to central changes (see Lewin et al., 1992b), whereas the heat hyperalgesia is likely to result at least in part from the sensitization of peripheral receptors to heat

Plasticity of the Group Ia Fiber Pathway to Motoneurons

This is a chapter in Changing Concepts of the Nervous System, which contains the proceedings of the First Institute of Neurological Sciences Symposium in Neurobiology, University of Pennsylvania, Philadelphia, PA