Extra

Slag Posten
(The Stroke Post)

aktuelt for og av medlemmer på Slaglisten
Slag PostenExtra nr.1 oppdatert/updated 31.nov.1998

Fra min bror har jeg mottatt en melding med flg. interessante artikkel om en mulig "kur" mot epilepsi!
                                                                    Trond Ruud
Artikkel i dagens Financial Times 15.08.98:

Protein Research

STROKE, EPILEPSY 'BREAKTHROUGH'

Researchers have cracked the three-dimensional structure of a key protein involved in stroke and epilepsy, paving the way for new drugs to treat these diseases.

Scientists from Vertex Pharmaceuticals published the finding in today's issue of Structure magazine. Researchers began to suspect that the protein - dubbed JNK3 - was implicated in stroke and epilepsy last year, when mice genetically altered to lack the enzyme proved immune to seizure. Stroke and epilepsy are closely related diseases; in fact , a stroke can lead a patient to develop epilepsy. Knowing the precise structure of the protein means scientsists can more readily design compounds to bind with and inhibit JNK3. (Reported by Victoria Griffith, Boston)

I tillegg fant jeg flg. idag i en press release fra Vertex Pharmaceuticals:
                                                                             Trond

Recent genetic research has highlighted JNK3's role in several neurological diseases. For example, mice bred to lack JNK3 have been shown experimentally to be highly resistant to seizure, a finding that implicates JNK3 in the pathogenesis of epilepsy. JNK3-deficient mice are also resistant to neuronal cell death resulting from glutamic acid release, a finding which suggests JNK3 involvement in stroke. Selective blockade of JNK3 activity therefore may be a useful strategy for treating these and other diseases.

Epilepsy and stroke are two of the diseases targeted by the JNK3 discovery effort. Epilepsy affects approximately 2.5 million people in the United States, and approximately 500,000 Americans each year suffer a stroke.

Og dessuten også flg. i en annen press release:

Cambridge, MA, August 24, 1998 - Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced today that they have signed a $88 million agreement with Schering AG, Germany to collaborate on the research, development and commercialization of novel, orally active neurophilin compounds to promote nerve regeneration for the treatment of a number of neurological diseases. Neurophilin compounds may play a future role in the treatment of a range of diseases, including peripheral neuropathies, Parkinson's disease, and spinal cord injury. Vertex's neurophilin compounds have been shown to accelerate functional recovery and promote nerve growth in several different animal models of central and peripheral nervous system injury...

Forskningsnytt fra Karolinska Institutet i Sverige, se:
http://www.mbb.ki.se/forsk/forsk.html

Studies on neurotrophic growth factors

In the nervous system the generation, survival, differentiation and degeneration of neurons is controlled by neurotrophic factors (Ibanez, Ernfors). The mechanisms of their action are studied using purified recombinant factors, genetically engineered cell-lines and gene targeting in transgenic animals. Recently, the role of neurotrophin-3 for early neurogenesis has been clarified. Also, structure function relationships for the interaction of neurotrophins with their receptors have been investigated. Thus a chimaeric protein with the biological activities of NGF, BDNF, NT-3 and NT-4, could be constructed. GDNF was shown to support survival and stimulate regeneration of neurons after brain damage! Such findings can become of importance for future treatment of for example Alzheimer´s disease.

REVERSING THE EFFECTS OF STROKE

Four years ago, the music stopped in Ronald Clark's life. A stroke left him paralyzed.

"I lost 100 percent on my left side," says Ronald. "There was no movement in my hand or my leg whatsoever."

A stroke a year ago landed Doris Nunn in a wheelchair, paralyzed on her right side. But now...

"I learned to walk down my ramp the other day," says Doris.

Both Doris and Ronald credit their recoveries to William Hammesfahr, M.D. Les artikkelen

REVERSING STROKE USING COMMON VASODILATORS

William M. Hammesfahr, M.D.
Donald D. Adkins, R.EEG T.

LAY ABSTRACT

Pasienter trenger nødvendigvis ikke lenger å reise til en spesialist for å bli utredet. Ved hjelp av ny datateknologi skal kompetansen heller gjøres tilgjengelig der pasienten er.
Aftenposten 15/9/98 iflg SOL hjemmeside
http://www.aftenposten.no/nyheter/nett/d52464.htm

Jeg fikk en link til flg. artikkel fra Hege før hun reiste på ferie: http://neuro-www.mgh.harvard.edu/forum/ChildNeurology

A hole in the Blood/Brain barrier ?

Research News

This article submitted by Judy on 9/5/98

Nose drops may improve treatment of brain diseases (og betydningen av å kunne tilføre nerve-vekstfaktorer til hjernen)

It said the nasal passage, which provides a direct link to the brain, could be the ideal conduit for delivering therapeutic drugs which cannot reach the brain through the blood.

The molecules of many drugs are so large they cannot cross the blood-brain barrier -- cells in the blood vessels in and around the brain that form a kind of barrier to guard brain tissue.

Finding an effective method of delivering drugs directly to the brain has been a stumbling block in treating neuro-
logical diseases.

The neuroscientist, William Frey of Alzheimer's Research Centre at the Regions Hospital in St Paul, Minnesota, thought nose drops could be an ideal way to get a new treatment for the disease, called nerve growth factor (NGF), into the brain.

"I knew that bad things could get in this way. It occurred to me that maybe good things could get in this way too,'' he said.

He and his colleagues tested the theory on 12 rats. Half were given NGF in nose drops and the rest in an injection. Within an hour of treatment Frey found that NGF given in nose drops had reached the hippocampus, amygdala and other regions of the rats' brains not involved in smelling.

In contrast, the rats that received injections had very little NGF in their brains.

"The nose, they say, could deliver drugs not only for Alzheimer's disease but for a range of other neuro- degeneratiave conditions as well, including Parkinson's disease and multiple sclerosis,'' the weekly magazine said.

Frey's team also used nose drops to administer insulin growth factor 1, a treatment for strokes, and found similar results. They will report their findings at a meeting of the American Association of Pharmaceutical Scientists in San Francisco in November.

The team, which has a patent on the idea, is also working with California-based biotechnology company Chiron Corp (CHIR.O) to develop it.

Copyright ©1998 Reuters Limited. All rights reserved.

Kommentarer

Ang. ovenstående er det interessant også å lese hva prof. Donald G. Stein (medforfatter av boken "Brain Repair") skriver om den mulige betydningen av å tilføre hjernen "nerve growth factors." Se hans  web side på: http://www.biomed.emory.edu/Faculty/Stein.html hvor han bl.a. skriver  flg.:

- As it became more evident that the "context" in which an injury occurs can determine functional outcomes, we began to explore other conditions and factors which could promote recovery after severe brain damage. For example, in the 1970's we demonstrated that intracerebral administration of nerve growth factor could enhance recovery after lesions of the caudate nucleus and could influence glial response to injury. At the time, we suggested that glia could promote recovery of function rather than simply contribute only to scar formation.

Men da de gjorde dette på 70-tallet ble altså vekst- faktorene tilført direkte inn i forsøksdyrenes hjerner. Og det har vel vært nettopp "blood/brain"-barriæren som har vært hinderet i å utprøve lignende tilførsel av vekstfaktorer for rehabilitering av hjerneskader også hos mennesker, antar jeg(?) Og derfor er det at "nesedråpe- metoden" til nevrologen William Frey virker så interessant.

Fylgj med fylgj med. No vert det spanande!...

Men det er mange ubesvarte spørsmål også, såsom:
- Vil tilførsel av vekstfaktorer kunne forårsake ukontrollert tilvekst av nerveforbindelser lignende de "hyssingnøstene" man finner bl.a. hos Alzheimer's pasienter?

Så det er nok et beite frem til den "slagkuren" som vi går og venter på, uansett! :-(
                                                                          Trond

For Immediate Release: 1 July 1998

Contact: Lauren Ward
wardla@a1.isd.upmc.edu
412-624-2607
University of Pittsburgh Medical Center

Contact: Mark Kanny
kanny@a1.isd.upmc.edu
412-624-2607
University of Pittsburgh Medical Center

LBS-Neurons For Treating Stroke

Physicians at the University of Pittsburgh Medical Center (UPMC) are evaluating the use of LBS-Neurons in the world's first clinical human neuron transplant into a patient's brain. This is the first effort to treat stroke patients with an intracerebral graft of cells. These neurons are provided by Layton BioScience, Inc., located in Atherton, Cal. Specifically, the Pitt research team expects the LBS-neurons to improve the function of neurons damaged after a stroke. Based on previous studies with an animal model of stroke, researchers think that grafted LBS-Neurons will either enhance the function of host neurons that survive a stroke but are impaired, or replace host neurons that have been destroyed by a stroke.

The LBS-Neurons are derived from a cell line initially developed in the mid-1980s and manipulated further in tissue culture and in animal models by several research teams from the late 1980s onward.

LBS-Neurons originate from a human teratocarcinoma found in a 22-year-old cancer patient. Teratocarcinomas are tumors of the reproductive organs that are composed of embryonic-like cells. Researchers at the University of Pennsylvania perfected and patented a process that uses several chemicals to cleverly transform this rapidly dividing cell line into fully differentiated, non-dividing neurons. They have accomplished this by treating the parent cells with retinoic acid, a biological agent known to induce the maturation of cancer cells into their normal-looking, noncancerous equivalents. This procedure has been used in other circumstances.

For example, cancer investigators have used retinoic acid to transform cancer cells in tumors of the head and neck cancer into benign or non-tumor cells as a therapy. Because teratocarcinomas contain cells that are embryonic in nature, they have the capacity to respond to treatment with specific chemicals by progressively developing into different cell types. Remarkably, the Layton BioScience line of teratocarcinoma cells obtained from the young patient differentiated into non-dividing neurons in response to the treatment discovered by the Penn researchers.

At the University of Pennsylvania, initial experiments using cultured LBS-Neurons revealed that they could thrive as transplants within normal rodent brains, as well as within stroke-damaged brain regions of rats. Researchers at Penn found that the LBS-neuron transplants within normal rodent brains integrated with existing neurons, produced other neuronal proteins and formed synapses.

Moreover, researchers investigating LBS-Neuron transplants in rodents found that these transferred cells started to look and function like the type of neurons near the insertion site. Thus, LBS-Neurons transplanted in the brain cortex became cortical neurons, whereas LBS-Neurons transplanted into deep brain regions resembled their neighbors. In some experiments, rats with LBS-Neuron grafts also received the immune-suppressing drug cyclosporin to block transplant rejection and promote the survival of the LBS-Neuron transplants for more than a year. However, grafts into the brains of mice with a limited functioning immune system also survived over one year without drugs to suppress the immune system.

Later experiments performed by other researchers at the University of South Florida showed that LBS-Neurons could correct cognitive deficits and motor skill problems associated with stroke-induced brain injury in rats. Significantly, all of these studies showed that the LBS-Neurons did not revert to cancer cells or cause tumors in any experimental animals.

In the current clinical trial at UPMC, investigators performed a single surgical procedure to deliver 2 million cells divided among three sites within and around the stroke-damaged tissue of the patient's brain.

Once implanted into and around the stroke, the LBS-Neurons are expected to integrate with existing tissue. There, they may restore brain function by interacting with the remaining neurons by mechanisms that are unknown, but which are under intense study.

The Pitt clinical investigators led by Douglas Kondziolka, M.D., and Lawrence Wechsler, M.D., will assess the activity of the implanted neurons 24 weeks after transplant using positron emission tomography, or PET, which will measure the metabolic activity, if any, in the area of the implanted nerve cells. Magnetic resonance imaging (MRI) sequences performed at 4 and 24 weeks after the transplant also will allow investigators to study the grafted brain site. In addition, the researchers will monitor blood levels of chemicals to assess for any adverse effects.

The use of LBS-Neurons in this clinical study obviates the need to use fetal cells, the other primary cell type being studied for transplant into the brain for a variety of other neurological disorders, such as Parkinson's disease and Huntington's disease. The harvesting of fetal human cells for treating disease has raised ethical concerns, especially regarding elective abortions. On the other hand, spontaneous abortions are rare and unpredictable events, so harvesting tissues from these fetuses would prove impractical. Further, cells from spontaneously aborted fetuses would be more likely to contain serious genetic defects.

The use of fetal animal cells has also been questioned, because cross-species transplantation involves animal tissue cells that carry very different immune markers from human tissue cells. Thus, cross-species immune rejection of the transplanted cells is likely. Moreover, fetal animal cells may contain as-yet unknown infectious diseases that could crossover into the recipient's tissue.

Another important feature of LBS-Neurons is that they can be frozen and transported to clinical centers for transplantation, whereas fresh (non-frozen) fetal cell cultures are used for transplantation. That LBS-neurons can be frozen, thawed and inserted into living brains at all is impressive. To date, researchers worldwide have been unable to achieve this level of progress with any other neuron cell line.

Many investigators contributed important pre-clinical research findings that made possible this historic clinical neuron transplant for stroke. For additional information about the history of the development and testing of LBS-Neurons, the pre-clinical application of LBS-Neurons to other disease processes and a corporate profile of Layton BioScience, Inc., please visit http://www.laytonbio.com.

For additional information about the role of these neurons in the clinical trial, please look in the News Bureau section of UPMC Health System's web page, http://www.upmc.edu.

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SlagPostenExtra nr.1 1998