Donald G. Stein

Pharmacological approaches to the treatment of brain and spinal cord injury

The pharmacological treatment of subjects who sustain a brain lesion, either accidentally (trauma, stroke) or surgically (tumor excision, stereotactic lesions, etc.) is generally aimed at preventing further damage from pathology such as edema, hemorrhage, infection. seizures, or renal or cardiopulmonary failure. The efficacy of these treatments can be observed in the period immediately following the insult. However, the long-term effects, if any, of these treatments, or any interactions between the drugs used and mechanisms involved in functional recovery, have often been ignored. A brief review of some basic aspects of the response of neural and nonneural cells to injury is offered, with some comments on events occurring during histogenesis and in the initiation and regulation of inflammatory and immune responses that might be relevant to the problem of brain plasticity. I then discuss some of the mechanisms of cell damage common to different forms of injury (e.g., trauma, hemorrhage, thrombosis) such as membrane permeability changes, intracellular calcium alterations, and the role of certain neurotransmitters in the genesis of acute neuronal loss. Special emphasis on ischemia is made, with a review of the pharmacological treatment of stroke and comments on the importance of the management of the medical and neurological complications of a brain lesion. I conclude with a discussion of the requirements in the design of clinical trials oriented towards the individualization of drug therapy. Finally, I summarize our own investigations with a pharmacological model of reversible brain dysfunction using GABA, an endogenous inhibitory neurotransmitter, in both rats and monkeys.

Extensive Loss of Subcortical Neurons in the Aging Rat Brain

We examined the number and size of neurons in subcortical structures of groups of rats that were 90 and 880 days of age. Our analysis revealed significant brain shrinkage as well as neuronal loss in the ventromedial and lateral hypothalamic nuclei (vmh and hl), the septum, the corticoamygdaloid nucleus, the substantia nigra, and the reticular formation. Only the lateral amygdaloid nucleus (alp) failed to show age-related cell loss. Furthermore, neuronal shrinkage could be observed in the vmh, hl, and alp. Although our analysis of subcortical structures was not exhaustive, the data indicate that the subcortical regions involved in the regulation of consummatory and emotional behaviors are as vulnerable to neuronal loss and atrophy as are cortical and cerebellar regions of the central nervous system.

Sparing and recovery of spatial alternation performance after entorhinal cortex lesions in rats

Groups of adult rats were first trained on a spatial alternation task and then subjected to unilateral entorhinal cortex lesions, unilateral entorhinal cortex lesions followed by dorsal psalterium transections, or bilateral entorhinal cortex lesions. After this surgery, the rats were then tested for retention of spatial alternation. Neither unilateral lesions alone nor unilateral lesions followed by dorsal psalterium transections resulted in long-term spatial performance deficits; however, animals with bilateral lesions exhibited severe impairments from which they eventually recovered. The results from animals with bilateral entorhinal damage indicate that extensive postoperative training may facilitate the recovery of spatial alternation performance. Histological analyses indicated that the crossed entorhinal projection proliferated in the dentate gyrus after unilateral entorhinal lesions and such anomalous growth occurred independently of any changes in alternation performance.

Fetal brain tissue transplant techniques: a cautionary note

Abstract The fact that embryonic brain tissue can be successfully transplanted into damaged brain of adult laboratory animals has many interesting and exciting implications for basic and clinical neuroscience. However, problems involving the degeneration of multiple brain systems in most neuro-denegerative diseases will likely limit the clinical usefulness of this technique. Furthermore, the question of whether aged or diseased brain can serve as a viable host organ has not been fully addressed. On the other hand, greater utility may exist in cases involving focal brain lesions. This may be particularly true in conditions not dependent upon complete or perfect re-innervation, and which may benefit more from the delivery of high concentrations of endogenous tropic factors. Of course, whether fetal tissue transplantation represents the most effective means of accomplishing this remains an issue for future study.

Nerve growth factor produces a temporary facilitation of recovery from entorhinal cortex lesions

Abstract Mature rats with entorhinal cortex lesions are impaired on learning a series of complex maze problems. A single, bilateral injection of NGF into the dorsal hippocampus caused an improvement during the initial maze learning, but it did not result in permanent recovery from the effects of the brain lesions. It is possible that chronic administration of NGF may have conferred more long-lasting functional recovery.

Degeneration in the spinal cord of old rats

Abstract Silver impregnation of spinal cords of young, adult, and old male Fischer 344 rats revealed an age-related loss of axons in the spinal gray and white matter. Beginning at 455 days of age, the animals showed degenerating fibers in the dorsal horn, intermediate gray, and ventral horn regions as well as in the fasciculus gracilis at the cervical, thoracic, and lumbar levels of the spinal cord. Axonal degeneration was not seen in the fasciculus cuneatus at any of the spinal cord levels examined. Degeneration was greatest in the gray matter of thoracic and in the dorsal columns of the cervical spinal cord levels. There were no differences in the quality of degeneration between the 15-, 17-, 24-, and 28-month-old animals.

Neonatal brain damage and recovery: Intraventricular injection of NGF at time of injury alters performance of active avoidance

Rats were given lesions of either the ventromedial hypothalamus (VMH) or septal nucleus at 7 days of age and then were tested repeatedly in an active avoidance task (A.A.) from 20 to 80 days. VMH rats were consistently impaired on the A.A. task beginning at 40 days of age. The animals with septal lesions performed the A.A. task consistently better than VMH or control animals throughout the entire test period, the septal syndrome becoming more pronounced as the rats reached maturity. In intact rats a single, intraventricular injection of NGF given at 7 days of age resulted in a greater reactivity, especially as the rats approached maturity. NGF, given at time of surgery, also improved performance of the A.A. task in VMH-damaged rats tested at 40-80 days. In rats given septal lesions, NGF treatment at time of injury attenuated the septal syndrome of improved A.A. performance. The data indicate that NGF treatment, given to neonatal rats, can produce long-lasting effects on CNS functions and can contribute to functional recovery from brain lesions.

Functional asymmetry of the songbird brain: Effects of testosterone on song control in adult female canaries (serinus canarius)

Previous research showed that chronic testosterone treatment of adult female canaries results in song development, demonstrating that vocal behavior is more dependent upon the presence of an appropriate hormonal stimulus than upon the genetic sex of the individual. We now report that in adult female canaries the importance of the left hemisphere for controlling testosterone induced song increases with singing experience. The occurrence of left-lateralized control of vocal behavior may prove to be a characteristic typical of animals capable of vocal learning.

A descriptive analysis of tail-pinch elicited eating-behavior of rats

Abstract Noninjurious tail-pinch (TP) reportedly elicits “a normal pattern of eating” from sated rats. The present investigation, however, revealed notable features of TP-elicited eating which distinguished it from food-deprivation (FD) elicited eating. For example, naive sated rats which were subjected to TP and offered familiar food in an unfamiliar setting ate more reliably than did naive rats subjected to FD. Presentation of an unfamiliar food (chocolate wafer cookies) resulted in TP rats dropping considerably more than they ingested, whereas FD rats ingested much more than they dropped. The present findings therefore indicate that TP may be more useful as a tool for assessing stimulus control of eating independent of depletion due to FD than as a model for “normal eating.”

Nerve growth factor disrupts metabolism and behavioral performance of intact rats but does not affect recovery from hypothalamic lesions

Although the biochemical 4 and morphologicaF effects of nerve growth factor (NGF) in peripheral and central nervous systems have been extensively studied and described, its behavioral consequences in intact or brain damaged subjects have not been as thoroughly investigated. In one experiment, however, Berger et al. z gave single, i.v. injections of NGF to adult rats that had suffered bilateral lesions of the lateral hypothalamus (LH). They found that the NGF treatments facilitated recovery of feeding after the lesions and conferred protection against reinstatement of aphagia and adipsia after intracerebral injections of the neurotoxin 6-hydroxydopamine (6OHDA). Single, intracerebral injections of NGF also attenuate some of the behavioral deficits that accompany bilateral damage to the caudate-putamen complex s, and most recently, we demonstrated that rats given 6-OHDA lesions of nucleus accumbens followed immediately by NGF injections near the substantia nigra, exhibit significant recovery of locomotor responses to D-amphetamine 1°. Taken together, these findings are interesting, but most behavioral studies have not conclusively shown whether the ameliorative effects of intracerebral NGF administration are dependent on prior brain perturbation or whether the NGF has a general activation effect on the behaviors that could be confounded with functional recovery 14. The general lack of information on the effects of central NGF administration to subjects without cerebral injury, prompted the present investigation. First, we attempted to evaluate some of the behavioral effects of i.v. NGF administration to intact, adult rats. Then, we studied the consequences of preand post-operative NGF treatments on recovery from deficits that accompany bilateral, simultaneous lesions of