Recent Patents on CNS Drug Discovery (Discontinued) - Volume 8, Issue 1, 2013

Stroke is a serious cerebrovascular disease that causes high mortality and persistent disability in adults worldwide. Stroke is also an enormous public health problem and a heavy public financial burden in the United States. Treatment for stroke is very limited. Thrombolytic therapy by tissue plasminogen activator (tPA) is the only approved treatment for acute stroke, and no effective treatment is available for chronic stroke. Developing new therapeutic strategies, therefore, is a critical need for stroke treatment. This article summarizes the discovery of new routes of treatment for acute and chronic stroke using two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF). In a study of acute stroke, SCF and G-CSF alone or in combination displays neuroprotective effects in an animal model of stroke. SCF appears to be the optimal treatment for acute stroke as the functional outcome is superior to G-CSF alone or in combination (SCF+G-CSF); however, SCF+G-CSF does show better functional recovery than G-CSF. In a chronic stroke study, the therapeutic effects of SCF and G-CSF alone or in combination appear differently as compared with their effects on the acute stroke. SCF+G-CSF induces stable and long-lasting functional improvement; SCF alone also improves functional outcome but its effectiveness is less than SCF+G-CSF, whereas G-CSF shows no therapeutic effects. Although the mechanism by which SCF+G-CSF repairs the brain in chronic stroke remains poorly understood, our recent findings suggest that the SCF+G-CSF-induced functional improvement in chronic stroke is associated with a contribution to increasing angiogenesis and neurogenesis through bone marrow-derived cells and the direct effects on stimulating neurons to form new neuronal networks. These findings would assist in developing new treatment for stroke. The article presents some promising patents on role of stem cell factor and granulocyte-colony stimulating factor in treatment of stroke.

Despite recent advances in cancer treatment and diagnosis, the prognosis for patients with CNS tumours remains extremely poor. This is, in part, due to the difficulty in completely removing tumours surgically, and also because of the presence of the blood brain barrier, which can prevent the entry of chemotherapeutic agents typically used in cancer treatment. Despite the presence of the blood brain barrier, tumour cells are capable of entering and colonising the brain to form secondary brain tumours. Additionally, tumour related disruption of the blood brain barrier is associated with the clinical presentation of many patients, with accompanying increases in intracranial pressure due, in part, to the development of vasogenic oedema. Vasogenic oedema results because the newly formed angiogenic vessels within brain tumours do not retain the highly selective properties of the blood brain barrier, and thus allow for the extravasation of plasma proteins and water into the brain parenchyma. Tachykinins, and in particular substance P, have been implicated in blood brain barrier disruption and the genesis of cerebral oedema in other CNS insults via a process known as neurogenic inflammation. Recent evidence suggests that substance P may play a similar role in CNS tumours. It has been well established that an upregulation of substance P and its receptors occurs in a number of different cancer types, including CNS neoplasms. In addition to disrupting blood brain barrier permeability, substance P and the NK1 receptors facilitate promotion of tumour growth and the development of cerebral oedema. Accordingly, recent patents describe the potential of NK1 receptor antagonists as anti-cancer agents suggesting that substance P may provide a novel cancer treatment target. This review will examine the role of substance P in the development of CNS tumours.

Current epilepsy therapy is still symptomatic using anti-seizure, rather than anti-epileptic, medications. This therapy may control the seizure activity but does not prevent or even cure epilepsy. Treatment strategies that could interfere with the process leading to epilepsy (epileptogenesis) would have significant benefits over the current approaches. Neuronal damage contributing to remodeling of the neuronal networks (such as in the hippocampus during temporal lobe epilepsy) is one of the significant components of ongoing epileptogenesis. Thus, treatment strategies alleviating seizureinduced neuronal damage and network reorganization may become powerful tools fighting the deteriorating process of epileptogenesis. Current anti-seizure medications, especially valproic acid, have some neuroprotective potential. Similarly, there is some hope of neuroprotection with newer anti-seizure drugs such as retigabine and levetiracetam. However, the neuroprotective potential of anti-seizure medications is frequently weak or masked by negative side effects associated with long-term treatment, therefore exceeding the benefits.. Thus, the attention is shifted to different compounds with already established neuroprotective potential. Among steroid hormones under investigation, two groups appear interesting: β-estradiol and selective estrogen receptor modulators – SERM. In low doses, β-estradiol has neuroprotective potency in neurodegenerative diseases. However, its use for seizure-induced neuroprotection is confounded by a common perception of proconvulsant features of estrogens. Here we review that both features, effects on neuronal excitability and neuroprotection, apply under specific conditions and may be separated by individualized therapy taking into account the dosage paradigm, timing, sex and age of the subjects and their gonadal hormone status (including progesterone: opposed vs. unopposed estrogen). Several studies have demonstrated that β-estradiol has indeed potency to protect neurons from seizureinduced damage. Additional studies are required to determine exact mechanisms of β-estradiol and SERMs in seizureinduced neuroprotection for truly individualized and effective therapy. The article presents some promising patents on anti-seizure medications.

The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective phytocannabinoid Δ9-THC produces analgesia and potentiates opioid analgesia in animal models, CB2 ligands studies aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB2 receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This review is an update of our previously manuscript “A survey of recent patents on CB2 agonists in the management of pain” and provides an overview of patents and advances in CB2 agonist studies in the treatment of pain.

Alzheimer's disease (AD) is a rapidly growing disease that is estimated to affect about 36 million people worldwide, therefore there is an immediate need for its' early diagnosis and treatment. A number of research studies are performed on possible accurate and reliable diagnostic biomarkers of AD. This review study provides an update on the cerebrospinal fluid (CSF) proteins that are being currently used in clinical practice and studied as biomarkers for early AD diagnosis and their future prospects, as well as relevant patents.

The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the hypothalamus-pituitary-adrenal (HPA) axis. Dysregulation in HPA activity (central and peripheral) has been reported in chronic diseases, like metabolic syndrome, type-2 diabetes mellitus, atherosclerosis-related disease, essential hypertension, dementia, depression, particularly during comorbid conditions. Different targets of anti-glucocorticoid treatment have been proposed, acting at supra-hypothalamic, HPA axis, glucocorticoid receptor and post-receptor levels. The recent promising patents on the therapy against glucocorticoid-mediated damage will be presented and discussed.