Daniele Tomassoni

Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease

Behavioural and psychological symptoms of dementia (BPSD) occur in 50-90% of Alzheimers disease (AD) patients. Imbalance of different neurotransmitters (acetylcholine, dopamine, noradrenaline and serotonin), involvement of specific brain regions responsible for emotional activities (parahippocampal gyrus, dorsal raphe and locus coeruleus) and cortical hypometabolism have been proposed as neurobiological substrate of BPSD. Compared to with respect to the neurochemical component, the cholinergic dysfunction seems to play a major role in contributing to BPSD occurrence. This view is also supported by the findings of recent trials with cholinesterase inhibitors, showing that these drugs are effective in controlling and/or improving BPSD, independent on effects on cognitive dysfunction. On the site of psychotropic drugs, atypical or novel antipsychotics represent the reference drugs for treating BPSD, whereas classic antipsychotic drugs for their profile and the potential side effects should be avoided.

The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia?

Hypertension is a main risk factor for cerebrovascular disease, including vascular dementia. The present study was designed to evaluate if hypertension-dependent changes of the hippocampus of spontaneously hypertensive rats (SHR) of different ages were related with those occurring in vascular dementia. The hippocampus was chosen as the brain area involved in learning and memory. Systolic pressure was slightly increased in 2-month-old SHR in comparison with age-matched normotensive Wistar-Kyoto (WKY) rats and augmented progressively with age in SHR. No microanatomical changes were observed in the hippocampus of SHR of 2 months in comparison with age-matched WKY rats. A limited decrease of white matter volume was observed in 4-month-old SHR. In SHR of 6 months, a reduction of grey matter volume both in the CA1 subfield and in the dentate gyrus occurred. Evaluation of phosphorylated 200-kDa neurofilament immunoreactivity revealed a decreased immune reaction area in the CA1 subfield of 6-month-old SHR compared to age-matched WKY rats and no changes in the expression and localization of the dendritic marker microtubule associated protein (MAP)-2. In 6-month-old SHR, an increase of glial fibrillary acidic protein (GFAP)-expression was found by Western blot analysis. Immunohistochemistry revealed an increase in number (hyperplasia), but not in size of astrocytes. These findings indicate the occurrence of cytoskeletal breakdown and astroglial changes primarily in the CA1 subfield of the hippocampus of SHR of 6 months. The occurrence in the hippocampus of SHR of regressive changes and astroglial reaction similar to those occurring in neurodegenerative disorders with cognitive impairment suggests that they represent an animal model of vascular dementia.

Protective effect of anti-hypertensive treatment on cognitive function in essential hypertension: analysis of published clinical data.

Hypertension is a risk factor for stroke and may also contribute to the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). Cognitive complications of hypertension and the influence of anti-hypertensive treatment were underestimated until recently. In this paper, trials investigating the effect of anti-hypertensive treatment on cognitive function were evaluated. Analysis of these studies revealed that until approximately 1990-1995 investigations have assessed primarily if anti-hypertensive treatment impaired cognitive function. Only more recent studies have investigated positive effects on cognition of anti-hypertensive medication. Drugs more extensively evaluated were diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, sartanes and Ca(2+) channel blockers. Available studies have confirmed that elevated diastolic blood pressure or pulse pressure and isolated systolic hypertension play an important role in the development of cognitive impairment. Randomized placebo-controlled trials have provided evidence that reduction of hypertension safely and effectively decreases morbidity and mortality rates and cognitive complications of hypertension. Ca(2+) channel blockers and ACE inhibitors have been shown to be effective and probably better than diuretics and beta-blockers on cognitive domains of hypertension. More extensive investigations could contribute to establishing optimal choice and drug dosage for the treatment of cognitive complications of hypertension.

Nimodipine and Its Use in Cerebrovascular Disease: Evidence from Recent Preclinical and Controlled Clinical Studies

Nimodipine is a 1,4-dihydropyridine-derivative Ca2+-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca2+-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospam in SAH patients.

Arterial Hypertension and Brain Damage—Evidence from Animal Models (Review)

Hypertension is an important risk factor for cerebrovascular disease including stroke and has also a role in the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). Research on pathophysiology and treatment of hypertensive brain damage may benefit from the availability of animal models. This paper has reviewed the main animal models of hypertension in which brain damage is documented. Spontaneously hypertensive rats (SHR) represent the animal model more largely used. In these rats cerebrovascular changes, brain atrophy, loss of nerve cells in cerebrocortical areas, and glial reaction were documented. Several changes observed in SHR are similar to those found by in vivo imaging studies in essential hypertensives. It is documented that brain gets benefit from lowering abnormally elevated blood pressure and that reduction of hypertension protects brain from stroke and probably reduces the incidence of VaD. The influence of anti‐hypertensive treatment on brain structure and function in animal models of hypertension is reviewed. Among classes of drugs investigated, dihydropyridine‐type Ca2+ antagonists were those with a most documented protective effect on hypertensive brain damage. Limits and perspectives in the use of animal models for assessing brain damage caused by hypertension and protection from it are discussed.

Glial fibrillary acidic protein immunoreactive astrocytes in developing rat hippocampus.

The developmental pattern of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes was investigated in the hippocampus (subfields CA1, CA3 and CA4) and in the dentate gyrus of male and female rats aged 11, 16, 30, 90 and 150 days by immunohistochemistry associated with image analysis. Analysis was centred on stratum radiatum, a hippocampal area rich in GFAP-immunoreactive astrocytes. The volume of different portions of hippocampus, the number and the size of astrocytes, the intensity of cell body GFAP immunostaining as well as the extension of astrocyte were assessed. A maturation pattern consisting in higher cellular expression of GFAP, an increase in overall cell size and expanding arborisation from the 11th to the 30th postnatal day, followed by stabilisation of these parameters until the 90th day of life, and a subsequent decrease in the oldest age group studied was found. A sex-related different temporal pattern of astrocytes maturation in size and GFAP content was observed in the CA1 subfield only. The increase of GFAP content during pre-weaning ages was less pronounced in females than in males as well as the decrease between the 90th and the 150th day of age. Moreover, the size of astrocytes was larger in females than in males at the 11th and 150th days of life. These findings suggest that hippocampal astrocytes undergo rapid maturation in the 1st month of postnatal life, followed by a slow consolidation of this process until the 3rd month of life. At 5 months of age, there are still dynamic changes in the mature astrocytes, which become slender and thinner probably as a response to the increased volume of hippocampus noticeable at this age.

Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats

Hypertension is the main risk factor for cerebrovascular disease including vascular dementia and control of blood pressure might protect from lesions causing cognitive impairment. The influence of anti-hypertensive treatment on hypertensive brain damage was assessed in spontaneously hypertensive rats (SHR). SHR and age-matched normotensive Wistar Kyoto (WKY) rats were treated from the 14-26th week of age with the dihydropyridine-type Ca2+ channel blockers lercanidipine, manidipine and nimodipine and as a reference with the non-dihydropyridine-type vasodilator hydralazine. Volume of brain areas, number of nerve cells and glial fibrillary-acidic protein (GFAP)-immunoreactive astrocytes and neurofilament 200 kDa immunoreactivity were investigated in frontal and occipital cortex and in hippocampus. In control SHR, systolic blood pressure (SBP) was significantly higher in comparison with WKY rats. Compounds tested decreased to a similar extent SBP values in SHR, with the exception of nimodipine that caused a smaller reduction of SBP compared with other compounds. Decreased volume and number of nerve cells and loss of neurofilament protein immunoreactivity were observed in SHR. GFAP-immunoreactive astrocytes increased in number (hyperplasia) and in size (hypertrophy) in the frontal and occipital cortex of control SHR, and only in number in the hippocampus. Anti-hypertensive treatment countered in part microanatomical changes occurring in SHR. Drugs investigated with the exception of nimodipine exerted an equi-hypotensive effect. In spite of this the best protection was exerted by lercanidipine and, to a lesser extent, by nimodipine. Compared with nimodipine, lercanidipine induced a more effective decrease of SBP. This may represent an advantage in the treatment of hypertension with risk of brain damage.

Treatment of Alzheimer's disease: From pharmacology to a better understanding of disease pathophysiology

Alzheimers disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence in the next future. It is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal loss affecting to a greater extent cholinergic neurons. A cascade of pathophysiological events is triggered in AD that ultimately involves common cellular signalling pathways and leads to cellular and neural networks dysfunction, failure of neurotransmission, cell death and a common clinical outcome. The process is asynchronous and viable neurons remain an important target for therapeutic intervention at each stage of disease evolution. At present symptomatic drugs inhibiting the degradation of acetylcholine within synapses and more recently glutamate receptor antagonists represent the mainstay of therapy. However, interventions able to halt or slow disease progression (i.e., disease-modifying agents) are necessary. Although much progress has been made in this area, there are currently no clinically approved interventions for AD classed as disease modifying or neuroprotective. This paper reviews the main symptomatic strategies available for treating AD and future strategies for improving our therapeutic approach to AD.

Increased Expression of Glial Fibrillary Acidic Protein in the Brain of Spontaneously Hypertensive Rats

Astrogliosis, consisting in astroglial proliferation and increased expression of the specific cytoskeletal protein glial fibrillary acid protein (GFAP) is common in several situations of brain damage. Arterial hypertension, which induces cerebrovascular changes, can cause also brain damage, neurodegeneration and dementia (vascular dementia). This study was designed to assess astroglial reaction in different brain areas (frontal cortex, occipital cortex, hippocampus and striatum) of spontaneously hypertensive rats (SHR) in the pre‐hypertensive phase (2 months of age), in the developing phase of hypertension (4 months of age) and in established hypertension (6 months of age). SHR were compared to age‐matched normotensive Wistar‐Kyoto (WKY) rats. Analysis included reverse transcription‐polymerase chain reaction (RT‐PCR) of GFAP mRNA, GFAP immunochemistry (Western blot analysis) and immunohistochemistry. A significant increase of GFAP mRNA and an increase of GFAP immunoreactivity were noticeable in different brain areas of SHR compared to normotensive WKY rats at 6, but not at 2 or 4 months of age. Immunohistochemistry revealed a numerical augmentation (hyperplasia) and an increase in size (hypertrophy) of GFAP‐immunoreactive astrocytes in frontal cortex, occipital cortex and striatum of SHR. In the hippocampus of SHR only a numerical increase of GFAP‐immunoreactive astrocytes was found. These finding demonstrating the occurrence of astrogliosis in the brain of SHR with established hypertension suggest that hypertension induces a condition of brain suffering enough to increase biosynthesis and expression of GFAP similarly as reported in several neurodegenerative disorders and in brain ischemia.

Dopamine, vesicular transporters and dopamine receptor expression and localization in rat thymus and spleen

The localization of dopamine stores and the expression and localization of vesicular monoamine transporter (VMAT) type-1 and 2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat thymus and spleen by immunohistochemical, immunochemical techniques and by RT-PCR. In the thymus dopamine immunoreactivity was developed in the cortico-medullary junction and in the medulla, but not in the thymic cortex. In the spleen, dopamine stores were found in reticular structures in the white pulp border and in the white pulp, but not in the red one. Both thymus and spleen expressed VMAT-1 and VMAT-2 immunoreactivity as well as dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity. Immunohistochemistry revealed VMAT-1, VMAT-2 and dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity primarily in the thymic cortical-medulla transitional zone and to a lesser extent in the medulla but not in the cortex. In the spleen, VMAT-1, VMAT-2 and dopamine D1, D2, D3, D4 and D5 receptor immunoreactivity was located primarily in the white pulp border and to a lesser extent in the white pulp. These findings indicate that both thymus and spleen express a dopaminergic system characterized by the presence of dopamine, vesicular monoamine transporters and the five subtypes of dopamine receptors. The presence of these dopaminergic markers suggests that dopamine likely originating from immune cells and/or from sympathetic neuroeffector plexus is released in the lymphoid microenvironment. Based on the microanatomical localization of dopaminergic markers investigated, a role of dopamine in maturation and selection of lymphocytes and activation of immune responses is suggested.