Role of the locus coeruleus catecholaminergic neurons in the chemosensory control of breathing in a Parkinson's disease model.

A previous study has demonstrated that in the 6-hydroxydopamine (6-OHDA)-model of Parkinson's disease (PD) there is a reduction in the number of Phox2b neurons in the retrotrapezoid nucleus (RTN) and a decrease in the respiratory response to hypercapnia 40days after PD-induction. The functional deficiency is restored 60days after 6-OHDA injection and here we tested the hypothesis that the locus coeruleus (LC) could be a candidate to restore the breathing deficiency. Minute Ventilation (VE) in response to hypercapnia (7% CO2) was assessed one day before, and then 40 and 60days after bilateral 6-OHDA (24µg/µL) or vehicle injections into the LC in control or PD-induced male Wistar rats. Bilateral injections of 6-OHDA decreased catecholaminergic neurons by 86% and 83% in the substantia nigra pars compacta (SNpc) and LC, respectively. As already described, in animals with lesions to the SNpc (N=6/group), the reduction in the ventilatory response to hypercapnia was restored 60days after PD (1257±81 vs. vehicle: 1185±49mL/kg/min). However, in animals with PD and lesion in the LC, the ventilation was blunted (674±39mL/kg/min). In another group of PD rats, we observed a reduction in the number of hypercapnia-induced-fos+ cells in the RTN region (40days: 38±3 and 60days: 8.5±0.9 vs. vehicle 78±3 cells) and an increase in the LC (40days: 46±4 and 60days: 94±22 vs. vehicle 1±1 cells). Our data suggest that LC catecholaminergic neurons can be a candidate structure mediating chemoreceptor function in a model of PD.

Progesterone prevents depression-like behavior in a model of Parkinson's disease induced by 6-hydroxydopamine in male rats.

Hemiparkinsonism induced by 6-hydroxydopamine (6-OHDA) injected in left corpus striatum is a recognized model of motor deficits in rats. Some reports concerning motor deficits indicate a favorable response to steroid administration in hemiparkinsonian animals. However, there is no much information regarding progesterone administration in relation to cognitive and affective dysfunctions. Here we could confirm earlier reports regarding a mild deficit of memory and a noticeable depressive-like behavior 4 weeks after injecting 6-OHDA. We also present some evidence that progesterone could be - when administered 7 days after the injection of 6-OHDA - a possible neuroprotector concerning both motor deficits as well as cognitive - memory- and depression-like behaviors. The affective deficit was reverted by administering the tricyclic antidepressant imipramine. Since Parkinson's disease is a conspicuous cause of psycho-organic decline in human beings, it would be important to be able of dealing early with non-motor indicators in order to use prospective neuroprotectors to prevent the progression of the disease.

Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson's disease.

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

The inter-relationships of tardive dyskinesia, parkinsonism, akathisia and tardive dystonia: the Curaçao Extrapyramidal Syndromes Study II.

A study of the four extrapyramidal syndromes (EPS), tardive dyskinesia, parkinsonism, akathisia and tardive dystonia, was performed in the Netherlands Antilles, a well-defined catchment area with only one psychiatric hospital. The population under study (N = 194; mean age 53.1) was mainly Afro-Caribbean, and most patients were chronic. The severity of each EPS was measured with valid and reliable rating scales. The purpose was to study both the strength of the inter-relationships of EPS and the prevalence of combinations of EPS. The inter-relationships between the EPS were analyzed by means of logistic regression. The adjusted odds ratios between the various EPS revealed strong connections between the hyperkinetic syndromes (tardive dyskinesia, tardive dystonia and akathisia). Parkinsonism was found to be inversely related to tardive dyskinesia and to tardive dystonia. Almost 30% of the patients suffered from two or more EPS. The highest prevalence rates of combinations were: tardive dyskinesia combined with parkinsonism 12.9%, tardive dyskinesia combined with tardive dystonia 9.8%, and tardive dyskinesia combined with akathisia 5.2%. Our findings show a strong positive correlation between hyperkinetic forms of EPS. Furthermore, chronic psychiatric inpatients regularly suffer from combinations of EPS. Different treatment strategies are suggested for various combinations of EPS.

Apraxia in Parkinson's disease, progressive supranuclear palsy, multiple system atrophy and neuroleptic-induced parkinsonism.

We studied 45 non-demented patients with Parkinson's disease (PD), 12 with progressive supranuclear palsy (PSP), 10 with multiple system atrophy (MSA) and 12 with neuroleptic-induced parkinsonism (NIP) for the presence of apraxia. Our aim was to determine whether a standard comprehensive assessment of different praxic functions would demonstrate specific types of errors not attributable to bradykinesia, rigidity, tremor or any other abnormal elementary motor deficit. PD patients on chronic levodopa treatment were examined in the 'on' and 'off' (treatment) states. Based on apraxia assessment scores, bilateral ideomotor apraxia for transitive movements was found in eight (75%) and 12 (27%) of PSP and PD patients, respectively. Ideomotor apraxia was mainly characterized by spatial errors (i.e., external and internal configuration, body-part-as-object and trajectory). Four PSP but no PD patients exhibited ideomotor apraxia for intransitive movements. PSP as well as PD patients with ideomotor apraxia also had difficulties in imitating hand and finger postures, but none of them failed on pantomime comprehension and pantomime recognition/discrimination. Some PSP patients exhibited, in addition, a limbkinetic type of apraxia and a minority of them displayed deficits on tasks involving multiple steps. Neither MSA nor NIP patients showed any disturbance of praxic functions. There were no differences in age, disease duration, Mini Mental State Examination (MMSE), Unified Parkinson's disease Rating Scale and Hoehn-Yahr scores between apraxic and non-apraxic PD patients, and ideomotor apraxia scores were similar in the 'on' and 'off' states. A correlation was found between ideomotor apraxia scores in PD patients and deficits in frontal lobe-related neuropsychological tasks such as the Tower of Hanoi, verbal fluency and the Trail Making Test. Furthermore, PD patients with apraxia showed higher Hamilton depression scores than non-apraxic PD patients. In PSP patients, ideomotor apraxia scores correlated significantly with cognitive deficit as measured with MMSE. The presence or absence of cortical involvement, and its severity and distribution might determine the presence and type of apraxia in PD and PSP. Apraxia in these conditions would therefore reflect combined cortico-striatal dysfunction.