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~ Huntington's Disease ~
Patents
US6630507 Neurological & Autoimmune Disorders; Cannabiniods as antioxidants & neuroprotectants
US6410588B1 1998-04-14 2002-06-25 anti-inflammatory agents The Mathilda And Terence Kennedy Institute Of Rheumatology Use of cannabinoids as anti-inflammatory agents
US6630507 Neurological & Autoimmune Disorders; Cannabiniods as antioxidants & neuroprotectants
US6410588B1 1998-04-14 2002-06-25 anti-inflammatory agents The Mathilda And Terence Kennedy Institute Of Rheumatology Use of cannabinoids as anti-inflammatory agents
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Preferred Strains
Preferred Methods to Medicate
Raw Kief/Greens
Ideally one should be eating Raw Kief/Greens for the A molecule THCA, CBDA etc, Over and above the preferred method of medicating, each cannabinoid & Terpenes plays a roll in healing.
Medicating
Ideally one should be eating Raw Kief/Greens for the A molecule THCA, CBDA etc, Over and above the preferred method of medicating, each cannabinoid & Terpenes plays a roll in healing.
Medicating
- Drops/Oil Dropped under tongue for faster absorption (Soft membrane tissue).
- Sprays, if for internal best applied through nasal sprays for soft tissue. (If Issue is eye's or ear's, apply to correlation)
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Overview:
Huntington's disease (HD), also known as Huntington's chorea, is an inherited disorder that results in death of brain cells.[4] The earliest symptoms are often subtle problems with mood or mental abilities.[1] A general lack of coordination and an unsteady gait often follow.[2] As the disease advances, uncoordinated, jerky body movements become more apparent.[1] Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk.[1][2] Mental abilities generally decline into dementia.[3] The specific symptoms vary somewhat between people.[1] Symptoms usually begin between 30 and 50 years of age, but can start at any age.[4][3] The disease may develop earlier in life in each successive generation.[1] About eight percent of cases start before the age of 20 years and typically present with symptoms more similar to Parkinson's disease.[3] People with HD often underestimate the degree of their problems.[1]
Genetics
All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (HTT). The gene is also called HD and IT15, which stands for 'interesting transcript 15'. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHTT). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant: mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene and hence its severity can be influenced by the sex of the affected parent.[24]
Genetic Mutation
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range.[25] The HTT gene is located on the short arm of chromosome 4[25] at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat.[25] CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region.[26]
THC reduces inducible huntingtin overexpression in PC12 cells, and both THC, CBD and endocannabinoids reduce inflammation.
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.[25] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[25] This altered form, called mutant huntingtin (mHTT), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.[17] Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD.[25] 36–39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed.[27] With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.[28]
Macroscopic changes
HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the basal ganglia called the neostriatum, which is composed of the caudate nucleus and putamen.[24] Other areas affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, the hippocampus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.[25] These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.[25] Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal pallidum being less affected.[25][42] HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.[43] Pathologic studies of HD show selective loss of CB1 (cannabinoid receptor).4 CB1 is found in the basal ganglia, cerebellum, dorsal primary afferent spinal-cord region and hippocampus
Transcriptional dysregulation
CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways.[41] Furthermore, the amino acids that form CBP include a strip of 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the HTT chain and CBP gets pulled away from its typical location next to the nucleus.[46] Specifically, CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain.[47] Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP.[46] In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.[41]
Some typical treatments
Improving cell survival
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.[131]
Neuronal replacement
Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.[140] Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.[141]
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.[131]
Neuronal replacement
Stem cell therapy is the replacement of damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments have yielded mixed results using this technique in animal models and preliminary human clinical trials.[140] Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.[141]
~ How Cannabis AIds ~
intro. cannabinoids Neuroprotective properties & HD Benefits via. Vanilloid TRPV(1), CB 1&2
intro. cannabinoids Neuroprotective properties & HD Benefits via. Vanilloid TRPV(1), CB 1&2
Pathologic studies of HD show selective loss of CB1 (cannabinoid receptor). CB1 is found in the basal ganglia, cerebellum, dorsal primary afferent spinal-cord region and hippocampus to mention a few.
The hypokinetic profile of certain cannabinoid agonists becomes these compounds as promising medicines to attenuate the hyperkinesia that characterizes the first grades of Huntington's disease (HD) and that represents the major neurological abnormality in this disease. The fact that CB(1) receptors, the receptor type involved in motor effects of cannabinoid agonists, are significantly reduced in the basal ganglia during the progression of HD represents a convincing explanation for the hyperkinesia typical of this disorder and supports the usefulness of enhancing CB(1) receptor signaling in HD. However, further studies revealed that the key property that enables certain cannabinoid agonists to reduce hyperkinesia is their capability to directly activate vanilloid TRPV(1) receptors. Cannabinoids may also serve to delay/arrest the progression of HD by protecting striatal projection neurons from death. Several cannabinoid agonists have been tested for this purpose in various animal models of HD, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection are three: (i) a reduction in inflammatory events exerted through activating CB(2) receptors located in glial cells; (ii) a normalization of glutamate homeostasis, then limiting excitotoxicity, an effect that would be exerted through CB(1) receptors; and (iii) an antioxidant effect exerted by cannabinoid receptor-independent mechanisms. The changes experienced by the endocannabinoid signaling system during the striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses proved by CB(2) receptors in glial cells recruited at lesioned sites.
The hypokinetic profile of certain cannabinoid agonists becomes these compounds as promising medicines to attenuate the hyperkinesia that characterizes the first grades of Huntington's disease (HD) and that represents the major neurological abnormality in this disease. The fact that CB(1) receptors, the receptor type involved in motor effects of cannabinoid agonists, are significantly reduced in the basal ganglia during the progression of HD represents a convincing explanation for the hyperkinesia typical of this disorder and supports the usefulness of enhancing CB(1) receptor signaling in HD. However, further studies revealed that the key property that enables certain cannabinoid agonists to reduce hyperkinesia is their capability to directly activate vanilloid TRPV(1) receptors. Cannabinoids may also serve to delay/arrest the progression of HD by protecting striatal projection neurons from death. Several cannabinoid agonists have been tested for this purpose in various animal models of HD, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection are three: (i) a reduction in inflammatory events exerted through activating CB(2) receptors located in glial cells; (ii) a normalization of glutamate homeostasis, then limiting excitotoxicity, an effect that would be exerted through CB(1) receptors; and (iii) an antioxidant effect exerted by cannabinoid receptor-independent mechanisms. The changes experienced by the endocannabinoid signaling system during the striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses proved by CB(2) receptors in glial cells recruited at lesioned sites.
~ CB 1 Receptor ~ Expression in HD
Cannabinoids activation of CB 1 Receptors Aids in HD Symptoms
Cannabinoids activation of CB 1 Receptors Aids in HD Symptoms
Having reduced CB1 receptors made HD symptoms appear four weeks earlier in the test subjects when compared with the HD subjects and the disease symptoms also progressed much more quickly. The CB1 deficit was also associated with a greater level of neuron loss in the striatum and a whole cascade of other problems with neuron structure. It was clear that these subjects were suffering due to the increased absence of cannabinoid receptors.
As a theraputic experiment, the researchers then tried to give THC (link is external) to the Huntingtin subjects (not the combined-type this time, that wouldn't do much since they don't have CB1 receptors though it would have been interesting to test other receptor effects like CB2). The reasoning went that if losing CB1 receptors made things worse then maybe activating those receptors more strongly in HD subjects would make their symptoms better - and it worked! Giving HD subjects THC improved their motor function, slowed the disease symptom progression, and improved the volume of their striatum.
As a theraputic experiment, the researchers then tried to give THC (link is external) to the Huntingtin subjects (not the combined-type this time, that wouldn't do much since they don't have CB1 receptors though it would have been interesting to test other receptor effects like CB2). The reasoning went that if losing CB1 receptors made things worse then maybe activating those receptors more strongly in HD subjects would make their symptoms better - and it worked! Giving HD subjects THC improved their motor function, slowed the disease symptom progression, and improved the volume of their striatum.
~ THCA & PPARy Pathways ~ Neuroprotectant
Cannabis aiding Huntington's in it's acidic form through the modulation of PPARy pathways
Cannabis aiding Huntington's in it's acidic form through the modulation of PPARy pathways
Studies have assessed possible neuroprotective actions of Δ9‐THCA through modulation of PPARγ pathways.
The effect of Δ9‐THCA on mitochondrial biogenesis and PPARγ coactivator 1‐α expression was investigated in Neuro‐2a (N2a) cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt‐q94).
Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9‐THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt‐q94 in N2a cells. Δ9‐THCA, through a PPARγ‐dependent pathway, was neuroprotective in mice treated with 3‐NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ9‐THCA attenuated microgliosis, astrogliosis and up‐regulation of proinflammatory markers induced by 3‐NPA.
Δ9‐THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.
Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9‐THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt‐q94 in N2a cells. Δ9‐THCA, through a PPARγ‐dependent pathway, was neuroprotective in mice treated with 3‐NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ9‐THCA attenuated microgliosis, astrogliosis and up‐regulation of proinflammatory markers induced by 3‐NPA.
Δ9‐THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.
DNA, RNA, Gene Expression & Transcription
Cannabis working as DNA, RNA, & Gene regulators & messengers
Cannabis working as DNA, RNA, & Gene regulators & messengers
THC also reduces inducible huntingtin overexpression in PC12 cells,48 and both THC, CBD and endocannabinoids reduce inflammation. A key element in this CBD effect is the inhibitory control of NFkB signalling activity and the control of those genes regulated by this transcription factor (i.e.iNOS) [31,81]. (NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.[1][2][3][4][5] NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.[6][7][8][9][10][11] Which can directly, influence the inflammatory response and the degenerative mechanism in HD patients) inhibitory control of NFkB signalling maybe exerted by reducing the phosphorylation of specific kinases (i.e. p38 MAP kinase) involved in the control of this transcription factor and by preventing its translocation to the nucleus to induce the expression of pro-inflammatory genes[31]. Studies are showing NF-κB regulates learning and memory in part by modulating synaptic plasticity,[6][45] synapse function,[44][46][47] as well as by regulating the growth of dendrites[48] and dendritic spines. [47] However, it has been recently proposed that CBD may bind the nuclear receptors of the PPAR family, in particular the PPAR-g [38, 39] (Table1) and it is well known that these receptors antagonize the action of NFkB ,reducing the expression of pro-inflammatory enzymes (i.e. iNOS, COX-2), proinflammatory cytokines and metal loproteases, effects that are elicited by different cannabinoids including CBD (reviewed in [9, 39]). Therefore, it could well be that CBD may produce its anti-inflammatory effects by the activation of these nuclear receptors and the regulation of their downstream signals although various aspects of this mechanism are pending further research and confirmation (see proposed mechanism in Figure1). Other mechanisms proposed for the neuroprotective effects of CBD include:(i) the contribution of 5HT1A receptors, e.g. in stroke [27, 28], (ii) the inhibition of adenosine uptake[37],e.g. in neonatalischaemia ([20], see below) and (iii)specific signalling pathways(e.g. WNT/b-catenin signaling) that play a role in b-amyloid-induced GSK-3b activation and tau hyperphosphorylation in Alzheimer’s disease
Clinical Studies