Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies.

An Appraisal of Vatsanābha (Aconitum Ferox Wall.) with Special Reference to Classical Texts Of Ayurveda: Saṁhitā, Cikitsā Grantha, Nighaṇṭus And Rasagrantha

Background: Vatsanābha, (Aconitum ferox Wall., Ranunculaceae), has been well documented in Ayurvedic texts such as Saṁhitā (treatise), Nighaṇṭu (lexicons), Rasagranthas (compendia related to alchemy) and Cikitsā granthas (compendia of Ayurveda). Methods: This paper provides a collective information regarding Vatsanābha, its morphological characters, properties and actions mentioned in Nighantu, Samhita and Rasagrantha. Result and discussion: The study reveals that Vatsanābha, a medicinal plant has about forty-one synonyms (paryaya); and highlightes its morphological characters and pharmacological properties. It is attributed with properties like Vyavāyī (CNS stimulation followed by depression), Balya (tonic), Rasāyana (Rejuvenation), Kaṇṭharukhara (reliever of throat pain), etc. As a single drug, Vatsanābha is indicated in about twenty-seven clinical conditions like Agnimāndhya (digestive impairment), Kāsa (cough), Madāvaha (alcoholism), Gulma (abdominal lump), etc. Vatsanābha is used for Śodhana (purification procedure), krāmaṇa (transformation of base metals into gold) and Vedhana (alchemy); 3 saṅskāra among the aṣṭasaṅskāra of pārada. Conclusion: This review may enrich to documentary research and may provide collective and detailed information regarding Vatsanābha as it is presented in ayurvedic classical texts.

Poisons affecting the neurological system

The brain is susceptible to a variety of poisons. Sedating drugs and chemicals can cause central nervous system (CNS) depression while other substances can cause CNS stimulation, including seizures. These are of particular concern since intractable seizure activity may cause complications, with pyrexia resulting in secondary damage to other organs. The common poisons discussed here that cause neurological effects are metaldehyde and tremorgenic mycotoxins, which can cause rapid onset seizures; cannabis, which can cause prolonged sedation in companion animals; permethrin, which is associated with prolonged seizures, particularly in cats; and ivermectin, which can cause CNS depression, blindness and seizures. Treatment is supportive in most cases; care should be taken when considering the use of emetics since there is a risk of aspiration in seizuring animals. Control of seizure activity is a priority, while intravenous lipid emulsion may also be useful.

Poisons affecting the neurological system

The brain is susceptible to a variety of poisons. Sedating drugs and chemicals can cause central nervous system (CNS) depression while other substances can cause CNS stimulation, including seizures. These are of particular concern since intractable seizure activity may cause complications, with pyrexia resulting in secondary damage to other organs. The common poisons discussed here that cause neurological effects are metaldehyde and tremorgenic mycotoxins, which can cause rapid onset seizures; cannabis, which can cause prolonged sedation in companion animals; permethrin, which is associated with prolonged seizures, particularly in cats; and ivermectin, which can cause CNS depression, blindness and seizures. Treatment is supportive in most cases; care should be taken when considering the use of emetics since there is a risk of aspiration in seizuring animals. Control of seizure activity is a priority, while intravenous lipid emulsion may also be useful.

Diet Drug Disaster: The Story of Redux and Fen-Phen*

The Fen-Phen Diet combines two FDA approved drugs. Although both drugs showed significant weight loss in controlled studies, no long-term studies of safety had been performed at the time of approval. It was thought that fenfluramine and dexfenfluramine, the active racemate of fenfluramine, suppressed appetite like other amphetamine-related drugs. Phentermine was thought to act as a balance to the adverse effects of abstinence from food and irritability from CNS stimulation caused by dexfenfluramine. Primary pulmonary hypertension (PPH) was known to be a rare risk at time of approval and prompted the recommendation that use be restricted to morbidly obese patients for short periods of time (6–8 weeks). An unanticipated danger of using these two drugs in combination is that together they can produce an overdosage of serotonin. The development of cardiac valvulopathies in otherwise healthy people recalled similar pathology in response to overdosage of serotonin from other medications or from a serotonin producing tumor of the Gl (carcinoid syndrome). Serotonin pharmacology is considered to illustrate the complexity of this remarkable chemical that has properties of neurotransmitter and hormone. Since this anorexogenic epidemic affected millions of patients and because there are potential permanent residual pathologies, pharmacists will continue to be queried about the topic. A review of the Redux/Fen-Phen history, pharmacology of the anorexigenics, and interactions with serotonin agonists and antagonists is presented to provide the pharmacist with a succinct and current account of this dark chapter in pharmacotherapy.