Cannabinoid extract in microdoses ameliorates mnemonic and nonmnemonic Alzheimer's disease symptoms: a case report.

BACKGROUND: Cannabinoid-based therapy has been shown to be promising and is emerging as crucial for the treatment of cognitive deficits, mental illnesses, and many diseases considered incurable. There is a need to find an appropriate therapy for Alzheimer's disease, and cannabinoid-based therapy appears to be a feasible possibility. CASE PRESENTATION: This report addresses the beneficial effect of cannabinoids in microdoses on improving memory and brain functions of a patient with mild-stage Alzheimer's disease. The patient is a 75-year-old white man presenting with main symptoms of memory deficit, spatial and temporal disorientation, and limited daily activity. The experimental therapeutic intervention was carried out for 22 months with microdoses of a cannabis extract containing cannabinoids. Clinical evaluations using Mini-Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale were performed. CONCLUSIONS: Here we provide original evidence that cannabinoid microdosing could be effective as an Alzheimer's disease treatment while preventing major side effects. This is an important step toward dissociating cannabinoids' health-improving effects from potential narcotic-related limitations.

Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?

Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.

Adenosine A1 receptor-dependent antinociception induced by inosine in mice: pharmacological, genetic and biochemical aspects.

Inosine is an endogenous nucleoside that has anti-inflammatory and antinociceptive properties. Inosine is a metabolite of adenosine, and some of its actions suggest the involvement of adenosine A1 receptors (A1Rs). The purpose of this study was to better understand mechanisms of inosine-induced antinociception by investigating the role of A1Rs and purine metabolism inhibitors. Inosine antinociception was evaluated using the formalin test in mice. An A1R-selective antagonist (DPCPX), A1R knockout mice (gene deletion) and mice with A1R reduced expression (antisense oligonucleotides) were used to assess the role of A1Rs in the antinociceptive action of inosine. Binding assays were performed to compare the affinity of inosine and adenosine for A1Rs. Finally, the role of adenosine and inosine breakdown was assessed using deoxycoformycin (DCF) and forodesine (FDS) as enzymatic inhibitors of adenosine deaminase and purine nucleoside phosphorylase, respectively. Inosine induced antinociception in the formalin test when given by systemic, spinal and peripheral routes. Systemically, inosine exhibited a potency similar to adenosine, and its effects were inhibited by DPCPX. Inosine did not induce antinociception in A1R knockout mice or in mice with reduced A1R expression. In binding studies, inosine bound to A1Rs with an affinity similar to adenosine. DCF had no effect on inosine actions. FDS augmented the antinociceptive effect of a low systemic dose of inosine and, at a higher dose, induced antinociception by itself. Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor.

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine.

Inosine is the first metabolite of adenosine. It exerts an antinociceptive effect by activating the adenosine A(1) and A(2A) receptors. We have previously demonstrated that inosine exhibits antinociceptive properties in acute and chronic mice models of nociception. The aim of this study was to investigate the involvement of pertussis toxin-sensitive G-protein-coupled receptors, as well as K(+) and Ca(2+) channels, in the antinociception promoted by inosine in the formalin test. Mice were pretreated with pertussis toxin (2.5 µg/site, i.t., an inactivator of G(i/0) protein); after 7 days, they received inosine (10 mg/kg, i.p.) or morphine (2.5 mg/kg, s.c., used as positive control) immediately before the formalin test. Another group of animals received tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (1 µg/site, i.t., a non-specific voltage-gated K(+) channel blockers), apamin (50 ng/site, i.t., a small conductance Ca(2+)-activated K(+) channel blocker), charybdotoxin (250 pg/site, i.t., a large-conductance Ca(2+)-activated K(+) channel blocker), glibenclamide (100 µg/site, i.t., an ATP-sensitive K(+) channel blocker) or CaCl(2) (200 nmol/site, i.t.). Afterwards, the mice received inosine (10 mg/kg, i.p.), diclofenac (10 mg/kg, i.p., a positive control), or morphine (2.5 mg/kg, s.c., a positive control) immediately before the formalin test. The antinociceptive effect of inosine was reversed by the pre-administration of pertussis toxin (2.5 µg/site, i.t.), TEA, 4-aminopyridine, charybdotoxin, glibenclamide, and CaCl(2), but not apamin. Further, all K(+) channel blockers and CaCl(2) reversed the antinociception induced by diclofenac and morphine, respectively. Taken together, these data suggest that the antinociceptive effect of inosine is mediated, in part, by pertussis toxin-sensitive G-protein coupled receptors and the subsequent activation of voltage gated K(+) channel, large conductance Ca(2+)-activated and ATP-sensitive K(+) channels or inactivation of voltage-gated Ca(2+) channels. Finally, small conductance Ca(2+)-activated K(+) channels are not involved in the antinociceptive effect of inosine.

Antinociceptive and gastroprotective actions of ethanolic extract from Pluchea sagittalis (Lam.) Cabrera.

ETHNOPHARMACOLOGICAL RELEVANCE: Pluchea sagittalis, an herbaceous plant widely distributed in South America, is used in folk medicine for the treatment of digestive diseases and inflammation. AIM OF THE STUDY: This study was designed to investigate the antinociceptive and gastroprotective effects of the ethanolic extract (EE) of aerial parts from Pluchea sagittalis in rodents. MATERIALS AND METHODS: The antinociceptive effects of EE was evaluated in mice after oral administration in chemical tests (acetic-acid, glutamate and formalin) or by biting behavior following intrathecal administration of cytokines such as interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) in mice. Furthermore, rats were treated with EE and subsequently exposed to acute gastric lesions induced by 80% ethanol. Afterwards the gastric lesion extension and the mucus levels of gastric mucosa were measured. RESULTS: The oral administration of EE showed a dose-dependent inhibition of acetic acid-induced abdominal constrictions and glutamate-induced pain in mice, with ID(50) values of 624.0 (523.0-746.0) mg/kg and 368.0 (216.0-628.0) mg/kg, respectively. In the formalin test, the EE also produced significant inhibition of the inflammatory phase, with an ID(50) value of 411.0 (183.0-721.0) mg/kg; however, it was ineffective in the neurogenic phase caused by formalin. In addition, oral treatment with EE caused a significant inhibition of biting behavior induced by i.t. injection of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The antinociception caused by the EE (300 mg/kg, p.o.) was not reversed by naloxone (1 mg/kg, i.p.) when assessed in the acetic acid writhing test. The EE (300-1000 mg/kg, p.o.) did not affect the motor coordination of animals in an open-field model. Oral treatment with the EE protected rats against gastric lesions induced by ethanol, with an ID(50) value of 55.0 (46.6-64.9) mg/kg, and increased the mucus levels of gastric mucosa to levels found in the non-lesioned group. CONCLUSIONS: The mechanism by which the extract produced antinociception still remains unclear, but this effect seems to be primarily related to the modulation or inhibition of the action of pro-inflammatory mediators. Furthermore, these data support, at least in part, the ethnomedical use of Pluchea sagittalis.

Evidence of TRPV1 receptor and PKC signaling pathway in the antinociceptive effect of amyrin octanoate.

Previous studies from our group investigated the antinociceptive property of amyrin octanoate, a synthetic compound derivative from natural precursor alpha, beta-amyrin, against nociceptive response induced by acetic acid and formalin. Here, we investigated some of the mechanisms of action underlying the antinociceptive effects of amyrin octanoate. Amyrin octanoate given intraperitoneally (0.001-1 mg /kg) or intrathecally (10-1000 ng /site) caused dose-dependent and long-lasting inhibition of acetic acid-induced visceral nociception, with mean ID(50) values of 0.003 (0.001-0.005) mg/kg and 122.4 (60.8-246.6) ng/site, respectively. In the capsaicin- and glutamate-induced paw licking, amyrin octanoate caused significant and dose-dependent inhibition of both nociceptive responses, with ID(50) values of 1.36 and 0.04 mg/kg, respectively. Furthermore, amyrin octanoate also reduced significantly the nociception caused by intrathecal injection of glutamate, substance P and capsaicin, with inhibitions of 36+/-11%, 67+/-10% and 78+/-5%, respectively. The antinociception caused by amyrin octanoate in the acetic acid test was significantly attenuated by neonatal pretreatment of mice with capsaicin, but seems to involve mechanisms independent of G(i/o) protein, opioidergic, serotonergic, noradrenergic and cholinergic system, since it was not affected by pertussis toxin, naloxone, yohimbine, mecamylamine or atropine. In addition, amyrin octanoate reduced thermal and mechanical hyperalgesia induced by bradykinin and phorbol myristate acetate in rats, without affecting similar responses caused by prostaglandin E(2). Taken together, the present results shown that octanoate amyrin produces antinociceptive and antihyperalgesic effects, through an interaction with capsaicin-sensitive fibers and the inhibition of the PKC signaling pathway.