What do they do?

From: Jeff Davis (jdavis@socketscience.com)
Date: Sun Jan 30 2000 - 08:17:13 MST


You're a neurosurgeon. A person comes in with an injury of the sort
described below. You are nearly certain, from your professional
experience, that the injury will result in profound and permanent
paralysis. But you have recently read the article below. Clinical trials
for humans are two years off.

What do you do?

 Purdue News

        February 2000

        Polymer repairs nerve damage
        in animals with spinal injuries

        WEST LAFAYETTE, Ind. A brief
        application of a polymer commonly used in
        medicine and cosmetics has been shown to
        immediately repair damaged nerve
        membranes in live guinea pigs with severe
        spinal cord injuries.

        The polymer, called polyethylene glycol or
        PEG, works by "fusing" the membranes of
        damaged nerve cells, and it can be applied
        up to eight hours after the injury without
        adversely affecting the patient's recovery.

        The process may someday be used in
        humans with spinal cord injuries to
        minimize or reverse the damage to nerve
        cells that results in paralysis, says Richard
        B. Borgens, professor of developmental
        anatomy at Purdue University.

        "It's the disruption of the membrane that
        leads to the death of the cell," Borgens says.
        "In this case, we're talking about a
        mechanical injury to nerve cells, which
        conduct the impulses needed for movement
        and a variety of other functions. If the nerve
        cell dies or separates, paralysis will
        occur."

        Borgens says this is the first study to
        demonstrate such a rapid recovery of
        function and nerve conduction in the whole
        animal with a spinal cord injury.

        He and his colleague, Dr. Riyi Shi, both of
        Purdue's Center for Paralysis Research in
        the School of Veterinary Medicine, report
        their findings in the January issue of the
        FASEB Journal, a publication of the
        Federation of American Societies for
        Experimental Biology. A year ago, they
        reported similar results in tests conducted
        on spinal cords that had been removed from
        guinea pigs.

        The findings offer the promise of rescuing
        substantial portions of damaged spinal cord
        at the time of initial surgery, Borgens says.
        The researchers plan to move the technique
        into clinical testing later this year, using
        paraplegic dogs with naturally occurring
        injuries.

        Because the treatment can be given up to
        eight hours after the injury without losing
        benefits, PEG may someday be used in
        addition to the drug methylprednisolone as
        an emergency treatment for spinal cord
        injuries, says Borgens.

        PEG is a nontoxic, water-soluble polymer
        widely used in medicine and cosmetics. In
        the study, Borgens and his team applied the
        substance across a region of the guinea pig's
        crushed spinal cord.

        "In most spinal cord injuries in animals and
        in people, the spinal cord is not completely
        severed, but is more likely to be crushed,"
        he says. "It is this crushing or compression
        of the spinal cord that causes the nerve
        fibers to develop holes in their membranes,
        which ultimately leads to cell death and
        separation of the nerve fiber within 24 to 72
        hours. If the nerve fibers separate, or
        otherwise do not conduct impulses,
        paralysis will occur."

        PEG was applied for two minutes, then
        removed. One group of animals received the
        application immediately after the injury,
        while a second group of animals was
        treated with PEG eight hours after the
        injury. Following the PEG applications, all
        the animals were tested to measure their
        ability to conduct nerve impulses through
        the spinal cord and to gauge their recovery
        of functional behavior.

        Nerve impulses through the spinal cord
        were measured by stimulating a nerve in the
        hind leg and determining whether and when
        the impulses arrived at the brain.

        Of the 47 guinea pigs used in the study, all
        25 of the animals that received PEG were
        able to recover some nerve conduction
        from 20 percent to 50 percent within 15
        minutes after PEG was applied.
        Measurements taken days and weeks later
        showed that, in addition, the nerve
        conduction recovery continued to improve
        up to one month after the initial treatment.

        Of the 22 animals that did not receive PEG,
        not one animal recovered the ability to
        conduct nerve impulses through the spinal
        cord, Borgens says.

        "Amazingly, one hundred percent of the
        PEG-treated animals recovered their ability
        to conduct nerve impulses, while none of
        the control animals did," Borgens says. "By
        measuring the quantity of nerve impulses
        that travel through the spinal cord, we can
        better index the integrity of the spinal cord
        after an injury."

        To analyze the animals' functional or
        behavioral recovery, Borgens and his group
        used a measure called "skin rippling," a
        behavior found in many animals but not in
        humans. Formally called the CTM reflex
        for cutaneous trunci muscle reflex the
        behavior can be observed as a corrugated
        rippling of back skin in response to light
        tactile stimulation, for example, when a
        cat's back is tickled or when a horse is
        assailed by flies.

        Borgens says the CTM reflex is an ideal
        tool for studying recovery of spinal injuries
        because the anatomy of the reflex is well
        understood and documented from the
        sensation of tickling on the skin to nerve
        impulses traveling up the spinal cord, to the
        motor nerves and back out to the skin.

        "We know all the connections, the complete
        circuit, and that's very powerful when
        tracking the flow of nerve impulses to see
        where they still exist or where they are
        blocked," he says. "Also, this is a behavior
        that is often permanently lost after severe
        spinal injury."

        To visualize and measure the CTM
        behavior prior to injury, the shaved back of
        each sedated guinea pig was touched lightly
        with a probe, producing contractions of the
        skin. The scientists used markers to indicate
        areas on the animals' backs that rippled in
        response to the stimulus. In addition, the
        process was videotaped to record the
        animals' behavior.

        The animals were videotaped again after the
        injury to show what part of the behavior
        was lost. After PEG was applied, the
        researchers used a pair of electrodes to
        stimulate nerve impulses through the spinal
        cord. In animals that showed behavioral
        recovery, the researchers compared the new
        movements with the videotapes made prior
        to the injury to measure the amount of
        recovery.

        "Only three of the sham-treated animals
        recovered some behavioral function after
        the injury, but overall they tended to get
        worse with time," Borgens says. "Twenty of
        the 25 animals treated with PEG recovered
        variable amounts of CTM functioning,
        which continued to improve with time."

        Borgens says the skin rippling test is a more
        reliable measure of post-injury behavior
        than tests designed to measure walking,
        because, unlike people, rats and some other
        animals can continue to walk after severe
        spinal cord injuries.

        "In rats and guinea pigs much of the process
        of walking is controlled at a specific
        location on the spinal cord, and is less
        dependent on nerve impulses traveling to
        and from the brain," he says.

        Though none of the animals showed a
        complete recovery of nerve conduction
        function, Borgens says that regaining 20
        percent to 50 percent of the function is
        significant.

        "If you have even 5 percent of the nerve
        fibers carrying nerve impulses, you'll get
        significantly more than 5 percent back in
        terms of restored behavior," he says.

        Borgens says the technique may be a
        revolutionary new way of dealing with
        injuries to the nervous system: "It's too soon
        to know whether it would help patients with
        old injuries, but it is likely to be useful in
        treating recent injuries."

        Borgens and Shi plan to conduct clinical
        trials in natural cases of paraplegia in dogs
        sometime this year. Human clinical trials
        are at least two years away.

        The research was sponsored by the state of
        Indiana, through support of the
        Purdue-Indiana University Institute for
        Applied Neurology, and through gifts from
        Helen Skinner and Mary Hulman George.

        Source: Richard Borgens, (765) 494-7600;
        cpr@vet.purdue.edu

        Writer: Susan Gaidos, (765) 494-2081;
        sgaidos@purdue.edu

        Purdue News Service: (765) 494-2096;
        purduenews@uns.purdue.edu

                    ABSTRACT
          Immediate recovery from spinal cord
         injury through molecular repair of nerve
                    membranes
               with polyethylene glycol
            Richard B. Borgens and Riyi Shi

        A brief application of the hydrophilic
        polymer polyethylene glycol (PEG) swiftly
        repairs nerve membrane damage associated
        with severe spinal cord injury in adult
        guinea pigs. A two-minute application of
        PEG to a standardized compression injury
        to the cord immediately reversed the loss of
        nerve impulse conduction through the injury
        in all treated animals while nerve impulse
        conduction remained absent in all
        sham-treated guinea pigs. Physiological
        recovery was associated with a significant
        recovery of a quantifiable spinal
        cord-dependent behavior in only
        PEG-treated animals. The application of
        PEG could be delayed for up to eight hours
        without adversely affecting physiological
        and behavioral recovery, which continued
        to improve for up to one month after PEG
        treatment.

                        Best, Jeff Davis

           "Everything's hard till you know how to do it."
                                        Ray Charles



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