The Role of Nanotechnologies in Brain Tumors.

The treatment of glioma remains one of the most interesting topics in neurooncology. Glioblastoma multiforme is the most aggressive and prevalent malignant brain tumor. Nowadays, technologies and new tools are helping the neurosurgeons to define a tailored surgery. However, there are few pharmaceutical strategies in operated and nonoperated patients. There are still few anticancer drugs approved by FDA and EMA. Moreover, these drugs are not so effective and have a lot of side effects due to their toxicity. Nanoparticles are a new strategy which could help to create and carry new drugs. In fact, NPs improve the pharmacokinetic properties of anticancer drugs, reduce side-effects, and increase drug half-life and its selectivity. Nanoparticle drug delivery system has been studied for targeting different molecular biomarkers and signaling pathways. Furthermore, the first problem of anticancer drugs in the treatment of gliomas is penetrating the blood brain barrier which represents an insurmountable wall for most of synthetic and natural particles. In the last 15 years, a lot of researches tried to design a perfect nanoparticle both able to cross blood-brain barrier and to selectively target glioma cells, unfortunately, without great results. In vivo human trials are still ongoing and many of them have already failed. In this chapter we evaluate the effectiveness of nanotechnologies in the treatment of brain tumors. There is not yet, currently, a nanoparticle drug designed for the treatment of gliomas approved by FDA and EMA. Advancements in discovery of molecular characteristics of tumors lead to the development of targeted nanoparticles that are tested in numerous in vitro and in vivo studies on gliomas. Novel and repurposed drugs, as well as novel drug combinations, have also been already studied but those are not included in this chapter because the carried drugs (active substances) are not included among the approved anticancer drug used in the treatment of gliomas.

Circulating miRNAs expression as potential biomarkers of mild traumatic brain injury.

TBI is the main cause of death and disability in individuals aged 1-45 in Western countries. One of the main challenges of TBI at present is the lack of specific diagnostic biomarkers, especially for mild TBI (mTBI), which remains currently difficult to value in clinical practice. In this context MiRNAs may be important mediators of the profound molecular and cellular changes that occur after TBI in both the short and the long term. Recently, plasma miRNAs profiling in human TBI, have revealed dynamic temporal regulation of miRNA expression within the cortex. Aim of this study was to select a specific miRNAs panel for mTBI, by focusing the research on the prognostic meaning of miRNAs in the hours following the trauma, in order to be able to use this MIRNAs as potential biomarkers useful for monitoring the follow up of mild TBI. Serum levels of 17 miRNAs were measured by RT-quantitative polymerase chain reaction (qPCR) in 20 patients with mTBI at three different time-points (0 h, 24 h, 48 h) and in 10 controls. For 15 miRNAs we found a significant differences in the comparison among the three time points: for each of these miRNAs the values were greater at baseline and progressively reduced at 24 h and 48 h. These data allow us to consider the miRNAs included in panel as sensitive and specific biomarkers for mTBI, useful in monitoring the post-trauma period.

ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies.

Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas.

Innovative Therapeutic Strategies in the Treatment of Meningioma.

Few medical options are available for progressive/recurrent and atypical/anaplastic meningiomas. New developments in chemotherapeutic options for meningiomas have been explored over the past decade. We review the more recent literature to recognize studies investigating recent medical and chemotherapeutic agents that have been experienced or are currently being tested for meningiomas. Combination therapies affecting multiple molecular targets are currently opening up and present significant promise as adjuvant therapeutic options. However, there is an evident need for new molecular studies in order to better understand the biology of meningiomas and, thus, to identify new and more specific therapeutic targets.

Typical trigeminal neuralgia by an atypical compression: case report and review of the literature.

AIM: Trigeminal neuralgia is a disabling form of facial pain that causes a considerable discomfort and a marked reduction in the quality of life. Although neurovascular compression is often associated with trigeminal neuralgia, other intracranial pathologies can result in compression along the nerve. CASE DESCRIPTION: The authors report a case of a patient suffering from a typical left trigeminal neuralgia affecting both the second and the third branches. Neuroradiological examinations showed the presence of an arachnoid cyst located in the left temporal lobe, contiguous with the Meckel's cave, eroding the greater wing of the sphenoid bone. Following a meticulous decision-making process the patient underwent conservative treatment with success. A properly modulation of the drug dosage allowed pain relief to be achieved. CONCLUSION: This is a rare case reporting a typical trigeminal neuralgia by an arachnoid cyst of the Meckel's cave mimicking a neurovascular compression syndrome. Our findings, behind the review of the current literature, point out the importance of such a pathological condition when dealing with patients affected by cranial nerve dysfunction syndrome.

Neuroprotective effect of erythropoietin and darbepoetin alfa after experimental intracerebral hemorrhage.

OBJECTIVE: Intracerebral hemorrhage (ICH) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its long-lasting analog, darbepoetin alfa, have been demonstrated to be neuroprotective in several models of neuronal insult. The objectives of this study were to analyze whether the systemic administration of recombinant human EPO (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery and brain damage in a rat model of ICH. METHODS: Experimental ICH was induced in rats by injecting autologous blood into the right striatum under stereotactic guidance. Subsequently, animals underwent placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Animals were killed 14 days after injury. RESULTS: Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment after injury, as assessed by the neurological tasks performed. rHuEPO- and darbepoetin alfa-treated animals exhibited a restricted brain injury with nearly normal parenchymal architecture. In contrast, the saline-treated group exhibited extensive cerebral cytoarchitectural disruption and edema. The number of surviving NeuN-positive neurons was significantly higher in the rats treated with rHuEPO and darbepoetin alfa compared with those that received saline (P < 0.05). CONCLUSION: These results demonstrate that weekly administered darbepoetin alfa confers behavioral and histological neuroprotection after ICH in rats similar to that of daily EPO administration. Administration of EPO and its long-lasting recombinant forms affords significant neuroprotection in an ICH model and may hold promise for future clinical applications.

Aneurysm clipping following endovascular coil embolization: a report of two cases.

BACKGROUND: Treatment of intracranial aneurysms by Guglielmi detachable coil (GDC) embolization is a useful therapeutic alternative to surgery. This procedure is attractive as a minimally invasive approach to treat cerebral aneurysms; however, is not devoid of complications or failure and retreatment, with either a surgical or endovascular technique, may often be required. CASE REPORTS: Two cases are presented in which surgery was required after coil embolization. In one case, surgical treatment was performed one month later because of regrowth and subsequent bleeding of the aneurysm. In the second case, surgical treatment was carried out six months later because of recanalization of the vascular malformation. Surgical treatment excluded both aneurysms from the cerebral circulation. CONCLUSIONS: In this paper the authors illustrate their experience and underline the difficulty of aneurysm surgery with coils in place.

The role of erythropoietin in neuroprotection: therapeutic perspectives.

Nervous system diseases are very complex conditions comprising a large variety of local and systemic responses. Several therapeutic agents interfering with all or in part the biochemical steps that ultimately cause neuronal death have been demonstrated to be neuroprotective in preclinical models. However, all the agents so far investigated have inexorably failed in the phase III trials carried out. A large body of evidence suggests that the hormone erythropoietin (EPO), besides its well-known hematopoietic action, exerts beneficial effects in the central nervous system. EPO's effect has been assessed in several experimental models of brain and spinal cord injury thus becoming a serious candidate for neuroprotection. The use of EPO as neuroprotectant raises several questions. Besides dosage and therapeutic time window, the safety of recombinant EPO administration in the setting of nervous system diseases takes priority over all other questions. Although recombinant EPO seems to be potentially safe at the neuroprotective proved doses, cardiovascular or cerebrovascular events can occur as a result of its bone marrow stimulating activities. The successful trial using EPO in patients with ischemic stroke and the large body of experimental evidence encourages intensive evaluation of this cytokine to support safe and larger clinical trials in the near future.

Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative.

OBJECT: Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO and carbamylated EPO have markedly improved functional outcome when administered after compressive SCI. However, an optimum treatment paradigm is currently unknown. Because the uninjured spinal cord expresses a high density of EPO receptor (EPOR) in the basal state, signaling through these existing receptors in advance of injury (pharmacological preconditioning) might confer neuroprotection and therefore be potentially useful in situations of anticipated damage. METHODS: The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t1/2 < 2 minutes), to EPO to determine whether a single dose (10 microg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPO or EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared with animals treated with saline solution. However, pretreatment efficacy was substantially poorer than efficacy of treatment initiated at the time of injury. Serum samples drawn immediately before compression confirmed that no detectable asialoEPO remained within the systemic circulation. Western blot and immunohistochemical analyses performed using uninjured spinal cord 24 hours after a dose of asialoEPO exhibited a marked increase in glial fibrillary acidic protein, suggesting a glial response to EPO administration. CONCLUSIONS: These results demonstrate that EPO and its analog do not need to be present at the time of injury to provide tissue protection and that tissue protection is markedly effective when either agent is administered immediately after injury. Furthermore, the findings suggest that asialoEPO is a useful reagent with which to study the dynamics of EPO-mediated neuroprotection. In addition, the findings support the concept of using a nonerythropoietic EPO derivative to provide tissue protection without activating the undesirable effects of EPO.

Landmarks for vertebral artery repositioning in bulbar compression syndrome: anatomic and microsurgical nuances.

OBJECTIVE: The purpose of this study was to better elucidate the anatomic relationship between the vertebral artery (VA) along with its perforating vessels and the brainstem to develop anatomic guidelines that would be helpful when decompressing medulla oblongata compressed by the VA. METHODS: Microanatomy dissection was performed in six formalin-fixed cadaveric heads. The VA, posteroinferior cerebellar artery (PICA), anteroinferior cerebellar artery (AICA), and lower brainstem perforators were examined under magnification using a surgical microscope. The outer diameters of the VA, PICA, and AICA were measured. The distance between the VA, lying within the lateral cerebellomedullary cistern, and the medulla oblongata was quantified. The lower brainstem perforating vessels were examined in relation to their course, outer diameter, and length. RESULTS: In four of six brains, the left VA was dominant, presenting an outer diameter at least 0.8 mm larger than the contralateral VA. The average distance between the VA and the medulla oblongata was 3 mm. The perforating branches presented a mean outer diameter of 0.7 mm. In particular, perforators arising from the VA and PICA (Groups 1 and 2) presented an average outer diameter of 0.2 mm and an average length of 7 mm. Perforating vessels arising from the AICA and vertebrobasilar junction (Groups 3 and 4) presented an average outer diameter of 0.4 mm and an average length of 12 mm. CONCLUSION: This work provides new information that may be useful to minimize the risk of injury of perforators when operating on medulla oblongata compression by the VA.

Erythropoietin and erythropoietin receptor expression after experimental spinal cord injury encourages therapy by exogenous erythropoietin.

OBJECTIVE: Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. Recent studies have demonstrated that EPO and its receptor (EPO-R) are expressed in the central nervous system, where EPO exerts neuroprotective functions. Because the expression of the EPO and EPO-R network is poorly investigated in the central nervous system, the aim of the present study was to investigate whether the resident EPO and EPO-R network is activated in the injured nervous system. METHODS: A well-standardized model of compressive spinal cord injury in rats was used. EPO and EPO-R expression was determined by immunohistochemical analysis at 8 hours and at 2, 8, and 14 days in the spinal cord of injured and noninjured rats. RESULTS: In noninjured spinal cord, weak immunohistochemical expression of EPO and EPO-R was observed in neuronal and glial cells as well as in endothelial and ependymal cells. In injured rats, a marked increase of expression of EPO and EPO-R was observed in neurons, vascular endothelium, and glial cells at 8 hours after injury, peaking at 8 days, after which it gradually decreased. Two weeks after injury, EPO immunoreactivity was scarcely detected in neurons, whereas glial cells and vascular endothelium expressed strong EPO-R immunoreactivity. CONCLUSION: These observations suggest that the local EPO and EPO-R system is markedly engaged in the early stages after nervous tissue injury. The reduction in EPO immunoexpression and the increase in EPO-R staining strongly support the possible usefulness of a therapeutic approach based on exogenous EPO administration.

Cerebellar hematoma in a patient with Marfan syndrome.

BACKGROUND: Marfan syndrome is a connective tissue disorder affecting many structures, including the skeleton, lungs, eyes, heart and blood vessels. It is an autosomal dominant inherited disorder due to a mutation of a gene encoding fibrillin-1, which affects connective tissue. Few case reports have associated Marfan syndrome with vascular malformations of the brain and spinal cord. In this regard, association with intracranial aneurysm has been vaguely proposed. CASE REPORT: We report here a patient with Marfan syndrome who was admitted because of a sudden loss of consciousness. The patient underwent computed tomography (CT) examination, which disclosed a right intracerebellar hematoma. Cerebral angiogram did not demonstrate aneurysm or arteriovenous malformation (AVM), or evidence of any other vascular lesions or neoplasms in the posterior fossa. Conservative treatment was undertaken. The clinical course was uneventful and after 6 weeks the patient was discharged free of symptoms. CONCLUSIONS: Although patients with Marfan syndrome are at high risk of vascular abnormalities, a clear association with cerebral aneurysm has not yet been established. Our experience and the contrasting reports available in the medical literature strongly warrant further studies in order to better clarify this controversial association.

Assessment of human brain water content by cerebral bioelectrical impedance analysis: a new technique and its application to cerebral pathological conditions.

OBJECTIVE: Total brain water content changes in several cerebral pathological conditions and the measurement of brain water content are important for the selection of appropriate therapeutic procedures. We present a quantitative, in vivo, bioelectrical impedance analysis (BIA) method and propose its use for the accurate assessment of brain water content among human subjects. METHODS: Cerebral BIA is based on the conduction of an applied current in the brain parenchyma. Application of an excitatory current of 800 microA at 50 kHz, via two electrodes placed on the eyelids with the eyes closed, and detection of the voltage drop with two electrodes placed in the suboccipital region allow brain resistance and reactance to be measured. By means of an equation that considers cranial circumference and resistance, it is possible to quantify the total brain water content, expressed as the bioelectrical volume. Cerebral BIA was performed with a series of healthy volunteers (n = 100), for determination of average brain water content values. The method was then applied to 50 patients with brain tumors (n = 20), intracranial hemorrhage (n = 16), or hydrocephalus (n = 14), for assessment of changes in global brain water contents. Data were compared with those obtained for healthy volunteers. RESULTS: Statistically significant differences (P < 0.001) were observed between the two groups. Mean brain water content values (expressed as bioelectrical volume values) were 38.2 +/- 3.9 cm2/Omega for healthy volunteers and 67.7 +/- 13.1 cm2/Omega for patients with cerebral pathological conditions. Statistically significant differences (P < 0.05) were also observed among patients with cerebral pathological conditions. CONCLUSION: The results of this study suggest that BIA, applied to the cerebral parenchyma, is a valid method for the prediction of brain water contents under both normal and pathological conditions. However, further studies are needed to establish whether it is sensitive and reliable enough for future clinical applications.

Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage.

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 (n = 8), control; group 2 (n = 8), control plus placebo; group 3 (n = 8), control plus r-Hu-EPO; group 4 (n = 8), SAH; group 5 (n = 8), SAH plus placebo; group 6 (n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations (P < 0.001), and reduced vasoconstriction of the basilar artery (P < 0.05), ischemic neuronal damage (P < 0.001), and subsequent neurological deterioration (P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.

Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage?

OBJECT: Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH. METHODS: Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001). CONCLUSIONS: The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.