Jose M. Rabey

AGMATINE TREATMENT IS NEUROPROTECTIVE IN RODENT BRAIN INJURY MODELS

Agmatine is a naturally occurring guanidino compound, found in bacteria and plants, with several proposed nervous system-related functions suggestive of beneficial effects in central nervous system injury. Here evidence is presented that agmatine can exert potent neuroprotection in both in vitro and in vivo rodent models of neurotoxic and ischemic brain injuries. The cumulative evidence lead us to suggest that agmatine, a relatively nontoxic compound, be tried for potential therapeutic use after neurotrauma and in neurodegenerative disorders.

Accelerated recovery following polyamines and aminoguanidine treatment after facial nerve injury in rats

Accelerated axon regeneration is of paramount importance for improved functional recovery after motor nerve injuries. Following injury of their axon neurones undergo a series of changes, termed the axon reaction, aimed at survival and regeneration of a new axon. We and others have found that early treatment with exogenous polyamines can enhance neuronal survival and accelerate the rate of axon regeneration and functional recovery after sympathetic and motor (sciatic) nerve injuries. Results of the present study corroborate the previous findings and demonstrate that after facial nerve injury in adult rats, polyamine treatment can accelerate the early phases of motor function recovery (vibrissae movement). Treatment with aminoguanidine, an inhibitor of several oxidation reactions, produced a further improvement at the early phase of functional recovery. In the facial nucleus, the injury-induced transient reduction in the activity of the acetylcholine synthesizing enzyme choline acetyltransferase was not affected by the treatment. After nerve injury in 5-day-old male rats, polyamines and aminoguanidine treatment exerted a minor neuroprotective effect (127.6% surviving neurones compared to control). We conclude that polyamines and aminoguanidine may have therapeutic potential in the acceleration of recovery after nerve injuries.

Radiation Therapy of Metastatic Spinal Cord Compression. Multidisciplinary team diagnosis and treatment

Purpose: To evaluate the effectiveness of a multidisciplinary approach to spinal cord compression (SCC) in accordance with prospective protocol, providing a uniform approach to diagnosis, decision making concerning optimal treatment modality in any particular case of SCC, treatment performance and evaluation of treatment results. The SCC patients treated by radiation therapy are described.Materials and Methods: Patients with SCC were examined and treated by a multidisciplinary team consisting of a neurologist, radiologist, oncologist, orthopedic surgeon, and neurosurgeon. Seventy-nine patients for whom radiation was recommended received a 30u2009Gy radiation dose to a compression-causing mass and course of high dose dexamethasone. Three fractions of 5u2009Gy and 5 fractions 3u2009Gy each were delivered by Co60 or 8u2009MV photon beam in 12 days. Treatment outcome was essentially evaluated by ambulation capabilities which were considered to be the main problem of SCC. Changes in other neurologic motor, sensory and autonomic disturbances were also evaluated.Results: Seventy-two percent of the patients were already non-ambulatory at diagnosis. The first symptom was motor deficiency in only 33% of them while in all other cases it was pain. Ambulation capability was the main prognosticator of treatment outcome; 90% of patients who were ambulatory before treatment remained so while 33% of the non-ambulatory patients regained their ability to walk. The grade of motor disturbance was also an important variable: among the non-ambulatory patients, 50% of the paretic but only 14% of the plegic ones became ambulatory. Overall, 51% of the study patients were ambulatory after undergoing radiation. The ambulatory state after treatment was the main predictor for survival.Conclusion: Close cooperation of a multidisciplinary team in diagnosis and treatment according to the above protocol enabled the achievement of good results of radiation treatment in SCC. Early diagnosis and early treatment should further enhance therapeutic outcome.

Decreased (3H) quinuclidinyl benzilate binding to lymphocytes in Gilles de la Tourette syndrome

In spite of an unknown pathophysiology, it has been suggested that central dopaminergic hyperactivity exists in Gilles de la Tourette syndrome (TS). Cholinergic influences have also been postulated as a dopaminergic-cholinergic balance seems to be important in other movement disorders. If TS is due to alterations of cholinergic activity, this may also be expressed at postsynaptic levels. Recently, we showed that circulating lymphocytes may serve as useful peripheral markers reflecting induced alterations or inherent changes in muscarinic receptors in the central nervous system (CNS). In the present study, we compared the muscarinic binding characteristics in peripheral lymphocytes as measured by (3H) quinuclidinyl benzilate [(3H)-QNB] in 27 unmedicated TS patients, against 22 healthy (age and gender-matched) controls. B(max) and Kd values were determined using Lineweaver-Burke plots. The mean B(max) values in nontreated TS patients was markedly and significantly lower than in controls (10.59 +/- 8.4 versus 40.16 +/- 9.2 fmole/10(6) cells, p less than 10(-6), while Kd values were similar in both groups. Our findings suggest that changes in cholinergic receptors may play a role in the pathophysiology of Tourette syndrome.

[3H]dopamine uptake by platelet storage granules in schizophrenia.

[3H]Dopamine (DA) uptake by platelet storage granules was determined in 26 schizophrenic male patients, paranoid type (14 acute stage; 12 in remission) and 20 age-matched, normal controls. Maximum velocity (Vmax) of DA uptake was significantly higher in acute patients, than patients in remission or controls (p less than 0.05). The apparent Michaelis constant (Km) of DA uptake in acute patients was also significantly different from chronic patients (p less than 0.05). Preincubation with reserpine (10(-4), 10(-5) M) produced a substantial diminution of DA uptake, while haloperidol (10(-4), 10(-5) M) did not affect the assay. Considering that a DA dysequilibrium in schizophrenia may be expressed not only in the brain, but also in the periphery and that an increased amount of DA accumulated in the vesicles, implies that an increased quantity of catecholamine is available for release, our findings suggest additional evidence for the role of DA overactivity in the pathophysiology of this disorder.

[3H] dopamine uptake by platelet storage granules in Parkinson's disease

[3H] Dopamine (DA) uptake by platelet storage granules was determined in 10 never-treated patients with Parkinsons disease (PD) (in 6 of them, also after 6 months of levodopa treatment), in 18 long-term levodopa-treated patients and in 15 age-matched normal controls. Maximum velocity (Vmax) of DA uptake was significantly lower in the group of never-treated PD subjects compared to healthy controls (P < 0.001) and also lower compared to the PD long-term treated patients (P < 0.025). The Vmax of PD never-treated changed after submitting the patients to 6 months treatment (P < 0.025) and became similar to the Vmax in the treated group. The apparent Michaelis constant (Km) of DA uptake in PD never-treated was also significantly different from controls (P < 0.005) and also different (but not significantly) from PD long-term treated patients. Decreased DA uptake by platelet storage granules in PD may reflect a generalized defect of dopaminergic cells with an impairment in the vesicularization of DA which may contribute to the symptomatology of this motor disease.

Decreased dopamine uptake into platelet storage granules in Gilles de la Tourette disease.

The movement disorder of Gilles de la Tourette (GdlT) disease may reflect hyperactivity of the basal ganglionic dopamine system. Since platelets have been suggested as peripheral models for the study of catecholamine neurons, we developed a method to measure the uptake of [3H]-DA into platelet storage granules (PSG). In the present report, PSG were incubated with [3H] DA, and Vmax and Km values were calculated by linear regression analysis (Lineweaver Burke plot). The uptake of DA (0.5-5 microM) by PSG from 18 GdlT patients was significantly lower (p < .0001) compared to 15 controls (Vmax mean +/- SD, 107.5 +/- 42.5 and 265.3 +/- 66.5 fmole/mg protein resp.). The decrease of DA uptake in GdlT may reflect compensatory presynaptic changes that reduce DA activity.

Plasma Dopamine Beta Hydroxylase (D.B.H.) activity in Parkinsonian patients under L-dopa, and 2-Bromo-alpha-ergocriptine loading

Dopamine-Beta-Hydroxylase (D.B.H.)-activity was measured in the plasma of untreated Parkinsonian patients, after treatment with L-dopa and 2-Bromo-alpha-ergocriptine. The findings were compared to the D.B.H.-activity of a matched healthy control group. After L-dopa loading D.B.H.-activity decreased in the Parkinsonian patients by 27.6±3.1% compared to 16.2±3.3% (p<0.02) in the control group. After 2-Bromo-alpha-ergocriptine loading the decrease in D.B.H.-activity was 32.6±4.4% in the Parkinsonian patients, and 158±4.9% (p<0.02) in the control group. This reduced D.B.H.-activity after L-dopa loading may reflect an impairment, in the Parkinsonian patients ability to metabolize L-dopa. The reduced D.B.H.-activity after treatment with 2-Bromo-alpha-ergocriptine may be explained by a pronounced antagonistic influence of 2-Bromo-alpha-ergocriptine on the presynaptic dopamine receptors, suggesting that presynaptic dopaminergic receptors are involved in Parkinsons disease.